Purpose: This study was conducted to assess and synthesize the current evidence on the association between rs12901499 polymorphism in SMAD3 gene and risk of osteoarthritis (OA). Materials and methods: Four electronic databases, including PubMed, Embase, ISI Web of Science, and CENTRAL were systematically searched for potential studies. Summary odds ratio and corresponding 95% CI were calculated to evaluate the association. Risk of bias was assessed through the Newcastle-Ottawa Scale. Subgroups and sensitivity analyses were performed using the RevMan 5.3 software. Publication bias was evaluated by Egger's and Begg's tests. Power analysis was conducted using the Power and Sample Size Calculation program. Results: Eight case-control studies containing 5,625 patients with OA and 5,600 healthy controls were obtained for the meta-analysis. After excluding cohorts with inadequate power, the pooled data supported that G allele carriers of rs12901499 had a significantly increased risk of OA (odds ratio 1.31, 95% CI: 1.21 to 1.43, P<0.00001). When stratified by OA site and ethnicity, the association remained statistically significant. Conclusion: The combined results evidently supported that rs12901499 polymorphism in SMAD3 gene is significantly associated with OA vulnerability across both Caucasian and Asian populations.