Background: Previous epidemiologic studies have shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased colorectal cancer risk. However, few studies have examined associations between NSAID use and subsite-specific colorectal cancer risks. Because tumors of the proximal and distal colon differ with respect to their genetic alterations, clinicopathologic features, and demographic distribution, further investigation of subsite-specific colorectal cancer risks may be rewarding. Methods: Data about aspirin and nonaspirin-NSAID use were recorded by self-report in 1992 among the initially cancer-free cohort of postmenopausal women in the Iowa Women's Health Study (n = 27,160). In total, 637 women developed colorectal cancer during the 11 years of follow-up, including 365 proximal colon, 132 distal colon, and 120 rectal cancer cases (11 overlapping and 9 not specified). Results: For colon cancer, the multivariable-adjusted hazard ratios (HR) for women reporting use of aspirin two to five times and six or more times weekly (compared with nonusers of aspirin) were 0.79 [95% confidence interval (95% CI), 0.59-1.04] and 0.76 (95% CI, 0.58-1.00), respectively. The corresponding HRs for nonaspirin NSAIDs were 0.63 (95% CI, 0.41-0.96) and 0.85 (95% CI, 0.63-1.15), respectively. For proximal colon cancer, the multivariable-adjusted HRs for women reporting use of aspirin or nonaspirin NSAIDs two or more times weekly (compared with nonusers of each) were 0.67 (95% CI, 0.51-0.87) and 0.71 (95% CI, 0.52-0.97), respectively. No statistically significant association was found between either distal colon or rectal cancer and aspirin or nonaspirin NSAID use. Discussion: Our study is consistent with a limited number of prior reports that have observed stronger associations between NSAID use and proximal versus distal colorectal cancer.