Objective: The objective of this review was to systematically review and synthesize evidence regarding benefits of using nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of colorectal cancer (CRC). Data Sources: The data sources were MEDLINE, PubMed, NEJM, Google Scholar, and Google searches of references from relevant and eligible trials. Review Methods: We screened abstracts and full-text articles of identified references for eligibility and reviewed randomized controlled trials, cohort studies, and meta-analysis for evidence on benefits of using NSAIDs in CRC treatments. For all extracted data, completeness and relevance were checked. Results: The risk of any adenoma among frequent NSAID users was 26.8% vs 39.9% among placebo subjects who later used NSAIDs sporadically (adjusted relative risk = 0.62, 95% confidence interval [CI] = 0.39-0.98; P trend with NSAID use frequency = .03). Long-term use of aspirin reduces the risk of CRC. Aspirin also reduces the incidence of colon adenomas and mortality, especially when used for >10 years. Rofecoxib is associated with the reduction of CRC; however, it was associated with cardiovascular risk (with an overall unadjusted relative risk of 1.50 [95% CI = 0.76-2.94; P = .24]). Adenoma Prevention with Celecoxib trial shows that, for patients of all genotypes, the estimated cumulative incidence of one or more adenomas by year 3 was 59.8% for those randomized to placebo as compared with 43.3% for those randomized to low-dose (200 mg, twice daily) celecoxib (relative risk [RR] = 0.68; 95% CI = 0.59-0.79; P < .001) and 36.8% for those randomized to high-dose (400 mg, twice daily) celecoxib and 60.7% in placebo group (RR = 0.54; 95% CI = 0.46-0.64; P < .001). Conclusions: The use of COX-2 inhibitors both prior to and after diagnosis of CRC seemed to be mildly associated with the reduction in mortality of patients with CRC. Some literatures state that COX-2 inhibitors might play a synergistic role in adjuvant chemotherapy of FOLFOX regimen. Celecoxib was found to increase the radiosensitization of colon cancer cells.