The natural history of cryptosporidiosis was investigated during a waterborne outbreak among 1731 members of a drug rehabilitation community in Italy; 19.6% of the members were positive for human immunodeficiency virus (HIV). Demographic and clinical information and pre-outbreak serum samples were available. Clinical data were analyzed, stratifying the study population by HIV serostatus and CD4 cell count. The attack rate of clinical cryptosporidiosis was 13.6% among HIV-negative individuals and 30.7% among HIV-positive individuals, although in the latter, it varied according to CD4 cell count. Clinical symptoms and their duration were also related to CD4 cell count. Chronic symptoms were observed in only 16 individuals (15.4%), who all had <150 CD4 cells at the onset of the illness. Among a systematic sample of 198 individuals, 14.1% already had anti-Cryptosporidium antibodies before the outbreak, and 51.2% developed specific antibodies during the outbreak. The development and clinical manifestations of cryptosporidiosis were strongly influenced by the level of HIV-induced immunosuppression.