OBJECTIVE: To compare the efficacy and safety of topical nonsteroidal anti-inflammatory drugs (NSAIDs) against placebo and active controls for improving pain and physical function of patients with knee osteoarthritis (OA). We hypothesize that topical NSAIDs will be safe and effective for relieving symptoms in patients with knee OA. METHODS: The authors performed a systematic review according to the PRISMA guidelines, searching PubMed, EMBASE, and Cochrane databases. Randomized control trials that investigated topical NSAIDs that are widely available in many countries against both placebo and active controls in primary knee osteoarthritis were included. Studies that investigated other treatment modalities or treated nonspecific OA were excluded. A meta-analysis was performed to quantify the effect sizes and heterogeneity of the NSAIDs used. RESULTS: Upon initial search, 259 records were identified with 18 studies remaining after duplicate removal, abstract, and full-text screening. All NSAIDs demonstrated statistically significant reduction in at least one parameter of OA symptoms. The majority of included studies (66.7%) evaluated diclofenac. In the meta-analysis, standardized mean differences (SMD) of topical NSAIDs versus placebo were calculated and interpreted as having moderate effect size for improvement in pain (0.365, 95% confidence interval (CI) 0.240, 0.490) and physical function (0.354, 95% CI 0.268, 0.493). With regard to safety, studies that used patches or dimethyl sulfoxide (DMSO) in the carrier reported a higher incidence of adverse events (AEs) than other carriers. Skin AEs were higher in the treatment group than the placebo group and gastrointestinal AEs were lower in the treatment group than placebo. CONCLUSION: Topical diclofenac and ketoprofen are the most rigorously studied topical NSAIDs in the treatment of knee OA and have demonstrated the most significant reduction in pain and improvement of function. Ibuprofen was effective for pain relief and physical function improvement, but more high-powered studies are needed to make a confident comparison of efficacy. Additionally, the 'carrier' used to deliver the topical NSAID has an impact on the adverse event profile. This has safety implications for prescribers and pharmaceutical development. Topical diclofenac is widely available internationally and is the only topical NSAID approved for over-the-counter use in the US. It should be recommended to patients as a first-line conservative management for OA of the knee.