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To estimate the benefits and harms of interventions with and without surgery for musculoskeletal (MSK) conditions.Intervention systematic review with meta-analysis of randomized controlled trials (RCTs).MEDLINE, EMBASE, CINAHL, Web of Science, and CENTRAL, all up to January 7, 2021.RCTs (English, German, Danish, Swedish, and Norwegian) of interventions with and without surgery conducted in any setting for any non-fracture MSK condition in adults (mean age: 18+ years) evaluating the outcomes on a continuous (benefits) or count (harms) scale. Outcomes were pain, self-reported physical function, quality of life, serious adverse events (SAEs), and death at 1 year.Random-effects metaanalyses for MSK conditions where there were data from at least 2 trials.One hundred RCTs (n = 12 645 patients) across 28 different conditions at 9 body sites were included. For 9 out of 13 conditions with data on pain (exceptions include some spine conditions), 11 out of 11 for function, and 9 out of 9 for quality of life, there were no clinically relevant differences (standardized mean difference of 0.50 or above) between interventions with and without surgery. For 13 out of 16 conditions with data on SAEs and 16 out of 16 for death, there were no differences in harms. Only 6 trials were at low risk of bias.The low certainty of evidence does not support recommending surgery over nonsurgical alternatives for most MSK conditions with available RCTs. Further high-quality RCTs may change this conclusion.