We report factors associated with severe manifestations of histoplasmosis (such as shock, respiratory failure, and death) in patients with AIDS during an outbreak. Severe disease was present in 28 of 155 patients (17.9%). The following factors were associated with severe disease: black race (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2–6.2); hemoglobin level <9.5 g/dL (OR, 2.7; 95% CI, 1.2–6.4), partial thromboplastin time >45 s (OR, 3.1; 95% CI, 1.1–9.3); alkaline phosphatase level >2.5 times normal (OR, 3.4; 95% CI, 1.3–8.7); aspartate aminotransferase level >2.5 times normal (OR, 4.2; 95% CI, 1.7–10.0); bilirubin level concentration >1.5 mg/dL (OR, 9.2; 95% CI, 2.5–34.3); creatinine concentration >2.1 mg/dL (OR, 8.3; 95% CI, 2.2–31.9); and albumin concentration <3.5 g/dL (OR, 4.6; 95% CI, 1.3–16.4). Zidovudine use was associated with decreased risk of severe disease (OR, 0.3; 95% CI, 0.1–0.7). Multivariate analysis showed that a creatinine value >2.1 mg/dL (OR, 9.5; 95% CI, 1.7–52) and an albumin value <3.5 g/dL (OR, 4.8; 95% CI, 1.0–22) were associated with an increased risk of severe disease, and zidovudine therapy remained associated with a decreased risk (OR, 0.2; 95% CI, 0.1–0.6). Findings associated with severe histoplasmosis should be recognized early and the cases managed aggressively.