We determined the frequency and clinical nature of severe hyperglycemia in a university clinic for HIV-1-infected patients. The medical records of 1392 adult HIV-infected patients were reviewed for cases of severe hyperglycemia, defined as two or more serum glucose values >250 mg/dl or diabetes treatment during clinic care. Demographic information, family histories of diabetes mellitus, body weights, CD4+ lymphocyte counts, and use of corticosteroids, megestrol acetate, pentamidine, or didanosine were recorded for subjects meeting the case definition. Comparisons were made between preexisting diabetic (group 1) and incident hyperglycemic cases (group 2). Less than 2% of the total clinic population experienced severe hyperglycemia: 12 in group 1 and 13 in group 2. Group 2 had lower body weights (mean, 70.6 kg versus 90.0 kg; p < 0.05) and more advanced HIV disease (mean CD4 count, 79/mm3 versus 550/mm3; p < 0.05) than group 1. Group 2 cases had evidence of drug-associated hyperglycemia; four cases demonstrated hyperglycemia coinciding with large fluctuations in weight during megestrol therapy. Among megestrol recipients, cases did not differ from noncases in demographics, weight, or CD4 count. Severe hyperglycemia is uncommon in adult HIV-infected patients. Approximately one half of these patients have preexisting diabetic conditions; many of the remainder may have drug-induced hyperglycemia, especially as a result of corticosteroids or megestrol acetate.