If "despite" (or "in spite of") comes at the start of the sentence, use a comma to separate the phrase starting with "despite" from the rest.

Use a comma after an introductory phrase starting with "despite" (or "in spite of")

Despite all my hard work, I still failed the math exam.

Despite all my hard work I still failed the math exam.

When using "despite" (or "in spite of") in mid-sentence, a comma before "despite" is generally unnecessary.

I arrived on time despite the flight delay.

However, if the phrase that follows "despite" is not essential, place it between commas. Nonessential phrases can be easily removed without changing the meaning of the sentence.

China, despite its rapid modernization, continues to struggle with air pollution.

China despite its rapid modernization continues to struggle with air pollution.

Note that you can remove "despite its rapid modernization" in the example above without changing the meaning of the sentence.

1. Starting a Sentence With 'Despite'

"Despite" and "in spite of" are prepositions. They are followed by a noun or a noun phrase and can be used to introduce a sentence. As a general rule, an introductory phrase should be followed by a comma.

Despite what has been said by former observers, the government is trying to ease the restrictions.

Despite what has been said by former observers the government is trying to ease the restrictions.

However, the comma is optional if the introductory phrase is brief (three or four words), and the sentence is clear.

Despite her excitement Rebecca didn't say anything to anyone.

"Despite" and "in spite of" are used to show contrast. Both have the same meaning and are used in the same way.

Despite being a liberal, I do not support drug legalization.

In spite of being a liberal, I do not support drug legalization.

Using a comma with "although"

2. 'Despite' in Mid-sentence

In the middle of a sentence, we do not typically use a comma before "despite" (or "in spite of").

The health service is on the brink of collapse in spite of the ceasefire.

However, we should add a comma before and after a phrase introduced by "despite" to include "added information" (information that can be easily removed without changing the meaning of the sentence).

My team, despite playing well, lost the game.

My team despite playing well lost the game.

Note that we can take out the phrase "despite playing well" without changing the basic meaning of this sentence.

Commas before and after "regardless of"

When using commas to set off nonessential information in mid-sentence, add both commas; that is, do not omit one comma and leave the other.

I still love my husband, despite all his faults, because he supports me and takes care of me.

I still love my husband despite all his faults, because he supports me and takes care of me.

A period at the end of a sentence replaces the closing comma.

They didn't reply, despite reminders.

Use of comma with "while" and "whereas"

3. More Examples

Starting a sentence with an introductory phrase (comma)

• In spite of being conservative, I believe that gun control laws reduce easy access to dangerous weapons.
• Despite her arm injury, Alice finished the tennis match.
• Despite being called insane and eccentric, he didn't get mad.
• Despite all your healthy diet, it may just be that your pancreas does not make enough insulin.
• Despite this gloomy Monday, I feel happy today.

Starting a sentence with a brief introductory phrase (optional comma)

• Despite the criticisms she kept arguing that their policy was plain wrong.
• Despite its clarity people didn't understand the artwork.
• Despite her beauty she tried to avoid attention.
• Despite being smart Emma tried to hide her intelligence.
• Despite working hard I'm not being successful.

'Despite' in mid-sentence (no comma)

• The government seems unable to control the situation despite all its efforts.
• Mary persevered despite discouragement from those around her.
• The project is progressing successfully in spite of current financial constraints.
• Real Madrid lost the match despite an excellent start.
• We had a good time in spite of the bad weather.

'Despite' in mid-sentence (commas)

• However, despite those substantial achievements, our project is lagging behind schedule.
• She is talented, intelligent, and beautiful, despite being rude.
• If you can't lose weight, despite all your efforts, try a different approach.
• I made a fortune, despite not working too hard, by creating a new software.

4. Conclusion

Follow these simple guidelines to punctuate "despite" or "in spite of" in a sentence:

1. In general, use a comma after an introductory phrase starting with "despite". You can omit the comma if the introductory phrase is very short and clear.
2. Do not use a comma before "despite" to introduce essential information.
3. Enclose in commas the phrase introduced by despite to add nonessential information (information that can be removed without changing the meaning of the sentence).