The incidence of acute respiratory failure (ARF) associated with cryptococcal disease in patients with AIDS is underestimated in the literature. We performed a retrospective, case-control (referent) study to determine the prevalence of ARF associated with cryptococcal disease and analyzed associated factors. Potential cases of ARF were identified at four university-affiliated teaching hospitals from a cohort of 210 patients with AIDS who had positive cryptococcal antigen tests and/orCryptococcus neoformansisolated from any body site. Twenty-nine of the 210 (13.8%) had ARF associated with cryptococcal disease. Nineteen were thought to have respiratory failure due solely toC. neoformans.The demographic, clinical, laboratory, treatment, and outcome data of 19 cases of respiratory failure were compared with data for 20 patients without respiratory failure. In-hospital mortality was 100% and median survival was 2 days for cases, vs. 25% and >365 days, respectively, for referents. The clinical presentation was identical to that ofPneumocystis cariniipneumonia. In multivariate analysis, variables independently predictive of ARF in patients with cryptococcal disease were black race, a lactate dehydrogenase level of ≥500 IU/L, the presence of interstitial infiltrates, and the presence of cutaneous lesions. ARF with cryptococcosis in patients with AIDS is associated with disseminated disease and high mortality. The diagnosis frequently is not considered before death. Serum cryptococcal antigen testing is a sensitive and rapid screening method.