Opportunistic infections are a theoretical concern with the use of tumor necrosis factor antagonists, as these agents can impair host immunity. A 61-year-old man with rheumatoid arthritis being treated with only etanercept (soluble tumor necrosis factor receptor) and in remission from the rheumatoid arthritis presented with dorsal tenosynovitis of his right wrist. The synovitis was not improved by a local corticosteroid injection. Surgical exploration showed granulomatous inflammation, and cultures were positive for Mycobacterium marinum infection. Etanercept was discontinued 4 months after the hand infection started. The infection resolved completely with surgery and antibiotic therapy with clarithromycin 500 mg twice daily orally for 3 months. Although M. marinum infection was locally invasive, there was no systemic dissemination of the infection despite ongoing etanercept therapy for 4 months before it was discontinued. With more frequent use of this class of agents for rheumatoid arthritis and Crohn's disease, we caution physicians to be alert for the possibility of this kind of local opportunistic infection.