Abstract Background Myasthenia gravis is an autoimmune disease mediated by antibodies against proteins associated with the postsynaptic membrane of the neuromuscular junction. Several drugs may trigger an exacerbation of the disease. Melatonin supplements are widely used for the treatment of insomnia as they are well tolerated with few side effects. The role of melatonin in the immune system and its effects in autoimmune disorders remain uncertain. Case presentation We identified three patients in our referral centre from 2014 to 2019 who presented a worsening within days or weeks of starting melatonin. Two of them stopped the treatment without clinical improvement in the next week. Increasing dose of corticosteroids did not lead to clinical improvement in the next month and one of the patients was finally administered intravenous immunoglobulins. Conclusion Melatonin may trigger exacerbations of myasthenia gravis, probably due to an upregulation of the adaptive immune system and an interaction with the corticosteroids and other immunosuppressant treatments. We consider that melatonin should be administered with caution in these patients.