This randomized, double-blind, placebo-controlled trial aimed to evaluate the effectiveness of low-dose methotrexate in preventing atherosclerotic events among patients with stable atherosclerosis. The study included 4786 patients who had a history of myocardial infarction or multivessel coronary disease and either type 2 diabetes or the metabolic syndrome. The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The trial was stopped after a median follow-up of 2.3 years due to lack of evidence of a reduction in cardiovascular events with methotrexate compared to placebo. Methotrexate did not lower levels of interleukin-1β, interleukin-6, or C-reactive protein. The incidence rate of the primary endpoint was 4.13 per 100 person-years in the methotrexate group and 4.31 per 100 person-years in the placebo group (hazard ratio, 0.96; 95% CI, 0.79 to 1.16). Methotrexate was associated with elevations in liver enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers. The findings suggest that low-dose methotrexate does not reduce cardiovascular events in patients with stable atherosclerosis.This randomized, double-blind, placebo-controlled trial aimed to evaluate the effectiveness of low-dose methotrexate in preventing atherosclerotic events among patients with stable atherosclerosis. The study included 4786 patients who had a history of myocardial infarction or multivessel coronary disease and either type 2 diabetes or the metabolic syndrome. The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The trial was stopped after a median follow-up of 2.3 years due to lack of evidence of a reduction in cardiovascular events with methotrexate compared to placebo. Methotrexate did not lower levels of interleukin-1β, interleukin-6, or C-reactive protein. The incidence rate of the primary endpoint was 4.13 per 100 person-years in the methotrexate group and 4.31 per 100 person-years in the placebo group (hazard ratio, 0.96; 95% CI, 0.79 to 1.16). Methotrexate was associated with elevations in liver enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers. The findings suggest that low-dose methotrexate does not reduce cardiovascular events in patients with stable atherosclerosis.