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BACKGROUND: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for over 40 years, few data on adverse event (AE) rates derive from randomized placebo-controlled trials, where both causality and magnitude of risk can be inferred. OBJECTIVE: To investigate AE rates, risk, and risk differences, comparing LD-MTX to placebo. DESIGN: Pre-specified secondary analyses of a double-blind placebo-controlled randomized trial. SETTING: North America. PARTICIPANTS: Adults with known cardiovascular disease and diabetes or metabolic syndrome. INTERVENTION: Random allocation to LD-MTX (maximum of 20mg/week) or placebo. All subjects received folic acid 1mg per day for six days/week. MEASUREMENTS: The risk of specific AEs of interest as well as all AEs were compared across treatment arms, after blinded adjudication. RESULTS: 6,158 patients were enrolled and 4,786 randomized after an active run-in period; median follow-up was 23 months and median weekly dosage 16mg. Of the randomized subjects, 81.2% were male with a median age of 65.0 years and a median body mass index of 31.5 kg/m2. Of 2,391 subjects randomized to LD-MTX, 2080 (87.0%) experienced an AE of interest compared to 1951 of 2,395 (81.5%) randomized to placebo (HR 1.17, 95% CI 1.10 – 1.25). The relative hazards of gastrointestinal (HR 1.91, 95% CI 1.75 – 2.10), pulmonary (HR 1.52, 95% CI 1.16 – 1.98), infectious (HR 1.15, 95% CI 1.01 – 1.30), and hematologic (HR 1.15, 95% CI 1.07 – 1.23) AEs were elevated, comparing LD-MTX to placebo. With the exception of an increased risk of skin cancers (HR 2.05 (1.28, 3.28)), there was no difference between treatment arms for the risk of other malignancies, mucocutaneous, neuro-psychiatric, or musculoskeletal AEs. Renal AEs were reduced in subjects randomized to LD-MTX (HR 0.86, 95% CI 0.78 – 0.94). LIMITATIONS: The trial was conducted in non-rheumatic disease patients who tolerated LD-MTX during an active run-in. CONCLUSION: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer, gastrointestinal, infectious, pulmonary, and hematologic AEs, while renal AEs were decreased.