We report the case of a 53-year-old Caucasian woman who developed nodal melanoma metastasis under infliximab therapy 2 years after the removal of a nevoid melanoma, which was initially misdiagnosed as a benign compound nevus. This case illustrates the potential link between tumor necrosis factor (TNF)-α inhibition and the reactivation of latent melanoma. Furthermore, this case highlights the need for a complete skin examination before using anti-TNF-α therapy to rule out atypical malignant lesions or melanomas that can easily be missed because of presentations such as nevoid melanoma.