Previous studies have reported inconsistent findings regarding the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of fracture. We identified relevant studies by searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to October 20, 2010. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. We identified 12 studies: seven case-control studies and five cohort studies. A meta-analysis of these 12 observational studies showed that the overall risk of fracture was higher among people using SSRIs (adjusted odds ratio [OR] ¼ 1.69, 95% confidence interval [CI] 1.51-1.90, I 2 ¼ 89.9%). Subgroup analysis by adjusted number of key risk factors for osteoporotic fracture showed a greater increased fracture risk in those adjusted for fewer than four variables (adjusted OR ¼ 1.83, 95% CI 1.57-2.13, I 2 ¼ 88.0%) than those adjusted for four or more variables (adjusted OR ¼ 1.38, 95% CI 1.27-1.49, I 2 ¼ 46.1%). The pooled ORs anatomical site of fracture in the hip/femur, spine, and wrist/forearm were 2.06 (95% CI 1.84-2.30, I 2 ¼ 62.3%), 1.34 (95% CI 1.13-1.59, I 2 ¼ 48.5%), and 1.51 (95% CI 1.26-1.82, I 2 ¼ 76.6%), respectively. Subgroup analysis by exposure duration revealed that the strength of the association decreased with a longer window of SSRI administration before the index date. The risk of fracture was greater within 6 weeks before the index date (adjusted OR ¼ 3.83, 95% CI 1.96-7.49, I 2 ¼ 41.5%) than 6 weeks or more (adjusted OR ¼ 1.60, 95% CI 0.93-2.76, I 2 ¼ 63.1%). Fracture risk associated with SSRI use may have a significant clinical impact. Clinicians should carefully consider bone mineral density screening before prescribing SSRIs and proper management for high-risk populations. ß