||OBJECTIVES: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been inversely associated with colorectal cancer; however, the association within colorectal subsites or among higher risk individuals is understudied. We investigated NSAID use and colorectal adenocarcinoma by subsite, and among individuals with a family history of colon cancer in the National Institutes of Health-AARP Diet and Health Study. METHODS: Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer incidence among 301,240 men and women (mean age 62.8 years); including 26,994 individuals with a first-degree relative with a history of colon cancer. We accrued 3,894 colorectal cancer cases during 10 years of follow-up; 372 cases had a first-degree relative with colon cancer. RESULTS: Both aspirin and non-aspirin NSAID use reduced colorectal cancer risk (HR for users compared with non-users=0.91, 95% CI: 0.85, 0.98; HR=0.82, 95% CI: 0.77, 0.87, respectively). Daily aspirin use reduced the risk of cancer in the distal colon (HR=0.84, 95% CI: 0.71, 0.99) and rectum (HR=0.76, 95% CI: 0.64, 0.90); daily non-aspirin NSAID use reduced the risk of both proximal (HR=0.65, 95% CI: 0.54, 0.78) and distal colon cancer (HR=0.69, 95% CI: 0.55, 0.87), but not rectal cancer. Among participants with a first-degree relative with colon cancer, daily use of aspirin was associated with a decreased risk of rectal cancer (HR=0.38, 95% CI: 0.19, 0.78), and daily use of non-aspirin NSAIDs was associated with a decreased risk of colon cancer (HR=0.49, 95% CI: 0.29, 0.82). No protective benefit for daily aspirin use and colon cancer or daily non-aspirin NSAID use and rectal cancer was observed in this higher risk subgroup, although power was limited by small case numbers. CONCLUSIONS: NSAID use was associated with a reduced colorectal cancer risk; the magnitude of this association differed between aspirin and non-aspirin NSAIDs. Daily aspirin and non-aspirin NSAID use by individuals with a family history of colon cancer significantly reduced the risk of rectal and colon cancer, respectively.