Advances in serologic assays for Cryptosporidium parvum have made serology an attractive surveillance tool. The sensitivity, specificity, and predictive value of these new assays for surveillance of immunocompromised populations, however, have not been reported. Using stored serum specimens collected for the San Francisco Men's Health Study, we conducted a case-control study with 11 clinically confirmed cases of cryptosporidiosis. Based on assays using a 27-kDa antigen (CP23), the serum specimens from cases had a median response immunoglobulin (Ig) G level following clinical diagnosis (1,334) and a net response (433, change in IgG level from baseline) that were significantly higher than their respective control values (329 and -32, Wilcoxon p value = 0.01). Receiver operator curves estimated a cutoff of 625 U as the optimal sensitivity (0.86 [0.37, 1.0]) and specificity (0.86 [0.37, 1.0]) for predicting Cryptosporidium infection. These data suggest that the enzyme-linked immunosorbent assay technique can be an effective epidemiologic tool to monitor Cryptosporidium infection in immunocompromised populations.