The two, both aged 19, were part of a larger group all understood to have taken the substance, and were found unconscious in Pryzm at around 1.40am on Saturday.
Police are investigating. They said no one else appears to be suffering ill effects of the substance.
Detective Inspector Julie Scoles said: “It is currently believed that the two men who died were part of a larger group who had taken what they thought to have been MDMA.
“Many of the group were from Okehampton and had visited Plymouth to attend the Basshunter set at the Pryzm nightclub last night.”
Inspector Scoles added: “We are not currently seeking anyone else in connection to this death, but would like to hear from anyone who has any information that can help us with our inquiries.
“I am urging the public, especially those going out and planning to take recreational drugs, to be aware of this incident and think twice before taking any unknown substance.
“There is always a risk when taking drugs and the only way of staying safe is to avoid drugs altogether.”
Devon and Cornwall Police have one man in custody and are not looking for anyone else in connection.
The DJ Basshunter, who was performing on Friday, posted on Twitter that he did not know what happened, but hoped “everyone is ok”.
Pryzm Nightclub said in a Facebook statement: “We are devastated by the events of this morning where two young men tragically lost their lives, and we would like to extend our thoughts and condolences to the families and friends at this very sad time.
“It is believed that earlier in the night the two men took what they thought to be MDMA and we would urge anyone, especially those going out tonight and who may be planning on taking recreational drugs, to be aware of this incident and to please think twice before taking any unknown substance.”
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They shared links to websites offering advice on drugs and also told anyone with information to share it with the police.
Anyone with information should contact the police on 101 or [email protected] quoting log number 67 for December 9, or through Crimestoppers on 0800 555 111.