A randomized, double-blind trial evaluated low-dose methotrexate (15–20 mg/week) versus placebo in 4786 patients with a history of myocardial infarction or multivessel coronary disease and type 2 diabetes or the metabolic syndrome. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. After a median follow-up of 2.3 years, methotrexate did not reduce cardiovascular events compared to placebo, with incidence rates of 4.13 vs. 4.31 per 100 person-years. Methotrexate also did not lower interleukin-1β, interleukin-6, or C-reactive protein levels. It was associated with elevated liver enzyme levels, reduced leukocyte counts, and a higher incidence of non-basal-cell skin cancers. The trial was stopped early due to lack of efficacy and no significant reduction in C-reactive protein. The results contrast with the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), where canakinumab reduced cardiovascular events. The study highlights the importance of targeting specific inflammatory pathways in atherosclerosis. Methotrexate, while effective in rheumatoid arthritis, did not show significant anti-inflammatory effects in this trial. The findings suggest that reducing cardiovascular events may depend on the specific inflammatory pathway targeted.A randomized, double-blind trial evaluated low-dose methotrexate (15–20 mg/week) versus placebo in 4786 patients with a history of myocardial infarction or multivessel coronary disease and type 2 diabetes or the metabolic syndrome. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. After a median follow-up of 2.3 years, methotrexate did not reduce cardiovascular events compared to placebo, with incidence rates of 4.13 vs. 4.31 per 100 person-years. Methotrexate also did not lower interleukin-1β, interleukin-6, or C-reactive protein levels. It was associated with elevated liver enzyme levels, reduced leukocyte counts, and a higher incidence of non-basal-cell skin cancers. The trial was stopped early due to lack of efficacy and no significant reduction in C-reactive protein. The results contrast with the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), where canakinumab reduced cardiovascular events. The study highlights the importance of targeting specific inflammatory pathways in atherosclerosis. Methotrexate, while effective in rheumatoid arthritis, did not show significant anti-inflammatory effects in this trial. The findings suggest that reducing cardiovascular events may depend on the specific inflammatory pathway targeted.