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Background: The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate. Objective: The objective of this study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of ≥1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. Methods: The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of ≥1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published. Results: For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46–1.51; versus naproxen: RR 1.49, 95% CI, 0.94–2.36; versus placebo: RR 1.08, 95% CI, 0.41–2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28–2.25; versus naproxen: RR 1.69, 95% CI, 0.82–3.48; versus placebo: RR 1.27, 95% CI, 0.25–6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35–2.35; versus naproxen: RR 1.42, 95% CI, 0.70–2.91; versus placebo: RR 0.59, 95% CI, 0.13–2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone. Conclusion: This meta-analysis of 34,668 patients receiving ≥1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).