Six out of seven cuttlefish acquired by the Smithsonian National Zoological Park in July 1998 died before 1 November 1998. Postmortem examinations showed mantle ulcers, secondary bacterial infections, inanition, and cuttlebone fractures. The surviving cuttlefish developed a progressive focal mantle ulcer, was treated with oral chloramphenicol intermittently for 9 wk, and maintained a normal appetite and growth rate until death at 7 mo of age. The National Zoological Park pathology database showed signalments, histories, and causes of mortality of 186 common cuttlefish, each 1–14 mo old, that received gross and histologic examinations; for example, the largest group of cuttlefish of known sex, age, and body weight at postmortem were 7–9 mo old and weighed an average of 376.2 g (males, n = 18) and 299.0 g (females, n = 15). Many cuttlefish had multiple pathologic diagnoses. Significant diseases included inflammation and secondary bacterial infections, especially gastrointestinal, cardiovascular, respiratory, reproductive, and ophthalmic, and septicemia due to Vibrio spp. or other gram-negative bacteria. Mantle lesions, including ulceration/dermatitis, abscess/granuloma, necrosis/fibrosis/cellulitis, and laceration/abrasion/erosion, were also identified, along with inanition, cuttlebone lesions, and trauma. Mantle lesions were associated with secondary bacterial infections and death. On the basis of this information, if captive cuttlefish behavior creates risk for development of mantle lesions, administration of antibiotics effective against gram-negative bacteria may delay or halt disease progression. Cuttlefish exhibits require proper design, husbandry, economic resources, and staffing to minimize disease syndromes and mortality.