We investigated the relative contribution of a pharmacogenomic measure of slow acetylation phenotype to susceptibility for bladder cancer in subjects with a history of high risk occupational exposure. The dapsone -acetylation was determined in 107 incident patients with transitional cell bladder cancer (organ-confined, non-aggressive cancer (n=43), organ-confined, aggressive cancer (n=32), non-organ-confined, aggressive cancer (n=32) and age, sex matched controls (n=85). Adjusting for age, sex, alcohol consumption and smoking habits, the slow acetylator phenotype and history of occupational exposure were independent; significant risk factors in at least one of the three subgroups of bladder cancer. In each cancer group, the combination of slow acetylation and occupational exposure conferred significant increases in risk with a synergistic substantially greater increase in non-organ-confined, aggressive bladder cancer. The frequency of occupational exposure and slow acetylator phenotype in the control group was 6% while this combination was present in 86% of patients with non-organ-confined, aggressive bladder cancer. These results support the hypothesis that slow acetylators exposed to high-risk occupations are at increased risk for the subsequent development of non-organconfined, aggressive bladder cancer.