An unusually aggressive Mycobacterium marinum infection of the hand that progressed despite surgical and medical treatment is presented. The infection progressed over a 3-week period after the patient had surgical treatment and received isoniazid (INH), rifampin, and ethambutol hydrochloride. The patient had a collar-button abscess, destruction of the metacarpophalangeal (MCP) joint capsule, flexor and extensor tenosynovitis, and metacarpal and proximal phalanx bone destruction at the MCP joint and metacarpal shaft. Although atypical mycobacterial infections of the hand are usually indolent but persistent, this Mycobacterium marinum hand infection progressed rapidly, even with surgical and medical treatment. A judgment was made to perform an index ray amputation. With a more complete excision of the infected tissue, there was a higher probability of controlling this severe infection. The patient was treated with antituberculosis medications for 6 months and is doing well 1 year after the operation.