Alternate day fasting (ADF; which consists of an ad libitum “feed day” alternated with a 75% energy restriction “fast day”) combined with exercise improves several coronary heart disease (CHD) risk factors. However, the effect of this combination therapy on endothelial function, and the role that adipokines play in mediating this effect, is unknown. Accordingly, this study examined the effect of ADF combined with exercise on brachial artery flow mediated dilation (FMD) and plasma adiponectin and leptin.Sixty-four obese subjects were randomized to 1 of 4 groups: 1) combination (ADF + endurance exercise), 2) ADF, 3) exercise, or 4) control, for 12 weeks.Body weight decreased (P < 0.05) in the combination (−6 ± 4 kg), ADF (−3 ± 1 kg) and exercise group (−1 ± 0 kg). Fat mass decreased (P < 0.01) in the combination (−5 ± 1 kg) and ADF (−2 ± 1 kg) groups. FMD increased (P < 0.05) only in the ADF group (5 ± 1% to 10 ± 2%; 5% increase). Leptin decreased in the combination (−34 ± 9 ng/ml, P < 0.001), ADF (−10 ± 4 ng/ml, P < 0.05) and exercise group (−11 ± 4 ng/ml, P < 0.05). Adiponectin was not changed by any intervention. Changes in FMD in the ADF group were not related to changes in leptin.These findings suggest that ADF alone is an effective intervention to improve vascular endothelial function. However, the role of adipokines in mediating this effect is still unclear.