OBJECTIVE Colorectal cancer (CRC) is the third most common cancer worldwide. Several preclinical and observational studies have shown that bisphosphonates may have chemopreventive effects against CRC. We performed a systematic review and meta-analysis of all studies evaluating the effect of bisphosphonates on the risk of CRC. METHODS We conducted a systematic search of Medline, Embase, and Web of Science through August 2012 and manually reviewed the literature. Studies were included if they met the following criteria: (1) evaluated and clearly defined exposure to bisphosphonates, (2) reported CRC outcomes, and (3) reported relative risks or odds ratio (OR) or provided sufficient data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model. Statistical heterogeneity was assessed with the Cochran's Q and I(2) statistic. RESULTS We analyzed data from 6 population-based observational studies reporting 20,001 cases of CRC in 392,106 patients. A meta-analysis of these studies showed a statistically significant 17% reduction in CRC incidence with bisphosphonate use (unadjusted OR, 0.83; 95% CI, 0.76-0.90), with borderline heterogeneity across studies (Cochran's Q, P = .16; I(2) = 37%). This effect persisted after correcting for multiple covariates in individual studies (adjusted OR, 0.85; 95% CI, 0.74-0.98). When the analysis was restricted to women only, use of bisphosphonates was associated with a 16% reduction in CRC incidence, which bordered on statistical significance (n = 5 studies; adjusted OR, 0.84; 95% CI, 0.70-1.01). This chemopreventive effect of bisphosphonates was observed for proximal and distal colon cancers, as well as rectal cancer, independently. CONCLUSIONS Based on meta-analysis, bisphosphonate use is associated with a modest, but statistically significant, reduction in CRC risk.