CB₁ antagonism is associated with reduced doxorubicin-induced cardiotoxicity and decreased cerebrocortical infarction. Rimonabant, a selective CB₁ receptor antagonist, was, before it was withdrawn, proposed as a treatment for obesity and reported to reduce cardiovascular risk by improving glucose and lipid profiles and raising adiponectin levels. The cardioprotective actions of rimonabant in 6-week-old C57BL/6J mice fed either high-fat (HFD) or standard diets (STD) for 8 weeks were investigated. At 14 weeks, mice received rimonabant (10 mg/kg/day, i.p.) or vehicle for 1 week and were then subjected to an in vivo acute myocardial infarction. The influence of rimonabant on infarct size (IS) in CB₁ knockout (CB₁−/−) and wild-type (CB₁+/+) mice was also examined. C57BL/6J mice that had been maintained on STD or HFD exhibited 4.3 and 21.4% reductions in body weight following 7 days rimonabant treatment. Rimonabant reduced IS in both STD (29.6 ± 3.5% vs. 49.8 ± 6.9% in control, P < 0.05) and HFD (26.9 ± 1.5% vs. 48.7 ± 7% in control, P < 0.05) mice. In CB₁−/− mice rimonabant failed to reduce body weight or IS (51.0 ± 5.3% vs. 49.7 ± 4.7% in control, P > 0.05), although significant reductions were seen in CB₁+/+ mice (IS, 48.9 ± 4.6% control vs. 30.5 ± 3.1% rimonabant, P < 0.05). To exclude the possibility that weight loss alone induced cardioprotection, HFD mice were switched to STD for 7 days (HFD–STD), resulting in an 11.3 ± 1.0% decrease in body weight compared to control (+2.1 ± 1.1% in HFD). This, however, was not associated with IS reduction (39.1 ± 3.9% HFD–STD vs. 40.0 ± 5.3% HFD, P > 0.05). Serum and cardiac adiponectin levels were unaltered by rimonabant treatment. HL-1 cell death was not prevented by 1 or 7 days treatment with rimonabant. We conclude that rimonabant-induced infarct limitation may involve the CB₁ receptor, although not necessarily cardiac CB₁ receptors, and is unrelated to weight loss or altered adiponectin synthesis.