We describe four patients with Mycobacterium marinum infections who did not respond to two- to six-week courses of therapy with tetracycline, minocycline, and doxycycline. All four patients had prompt responses to therapy with either rifampin alone (two patients) or rifampin in combination with ethambutol. Results of antimicrobial sensitivity tests may be helpful in guiding therapy. Rifampin may be the drug of choice for treatment of these infections.