Cell cycle regulation is mediated in part through expression of the cyclin-dependent kinase inhibitor p21 WAF1/CIP1. Loss of p21 WAF1/CIP1 expression may, therefore, contribute partially to schistosomal carcinogenesis in the urinary bladder. We compared p21 WAF1/CIP1 expression in schistosomal and nonschistosomal bladder cancer to explore possible differences in p21 WAF1/CIP1 expression between the two subtypes and the possible association between schistosomiasis and loss of p21 WAF1/CIP1 expression. Tumor specimens were obtained from 130 patients who underwent transurethral biopsy or cystectomy. p21 WAF1/CIP1 was determined by immunodot blot, Western blot, and enzyme immunoassay (EIA). We validated a highly sensitive quantitative EIA assay for determination of p21 WAF1/CIP1 in cell lysates. Precision, analytical recovery, and linearity were all excellent. Our results did not show any correlation between p21 WAF1/CIP1 expression and most clinicopathologic variables. Lower expression of p21 WAF1/CIP1 was evident in squamous cell carcinoma (SCC) and schistosomal subtype than in transitional cell carcinoma and nonschistosomal tumors. Our data suggest a potential role for p21 WAF1/CIP1 alteration in schistosomal carcinogenesis.