Cannabidiol (CBD) is a major, non-psychoactive cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling. As adenosine receptors are promising pharmaceutical targets for ischemic heart diseases we tested the effect of CBD on ischemic rat hearts. For the in-vivo studies the left anterior descending artery was transiently ligated for 30 minutes; the rats were treated for 7 days with CBD (IP, 5mg/kg) or vehicle. Cardiac function was studied by echocardiography. Infarcts were examined morphometrically and histologically. For the ex-vivo evaluation animals received CBD 24 and 1 hour prior to sacrifice, hearts were harvested for physiological measurements. In-vivo studies showed preservation of shortening fraction in CBD treated animals (from 48±8% to 39±8 % and from 44±5 % to 32±9 % in CBD and controls, respectively, n=14, P<0.05). Infarct size was reduced by 66% in CBD treated animals, despite nearly identical areas at risk (9.6±3.9% vs. 28.2±7.0% in CBD and controls, respectively, P <0.001) and granulation tissue proportion as assessed qualitatively. Infarcts in CBD-treated animals were associated with reduced myocardial inflammation and a reduction in IL-6 levels (254 ± 22 pg/ml vs. 2812 ± 500 pg/ml in the CBD and control respectively, p<0.01). In isolated hearts no significant difference could be detected between CBD-treated and control hearts in either infarct size, left ventricular developed pressures during ischemia and reperfusion or in coronary flow. Our study shows that CBD induces a substantial in-vivo cardioprotective effect from ischemia that was not observed ex-vivo. As CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.