We report an unusual case of disseminated dermatitis, osteomyelitis, and bacteremia in an immunocompromised host. An infant presented with a pustular skin rash resembling chicken pox, but culture of a skin lesion yielded Mycobacterium marinum. Upon further evaluation, severe combined immunodeficiency was diagnosed. Radiographs of the hands and feet showed evidence of osteomyelitis. M. marinum was isolated from blood and synovial fluid. We recommend a high level of suspicion for this organism in immunocompromised hosts who have been exposed to fresh water or salt water, particularly those of aquaria. Drug susceptibility testing of serial clinical isolates from our patient revealed development of high-level resistance to isoniazid and rifampin during therapy. We believe that treatment of disseminated M. marinum infections should include combinations of antimycobacterial agents chosen on the basis of results of susceptibility testing done by an experienced laboratory, thereby limiting the emergence of drug resistance.