The ability of alternate-day fasting (ADF) to modulate adipocyte parameters in a way that is protective against coronary heart disease (CHD) has yet to be tested. Accordingly, we examined the effects of ADF on adipokine profile, body composition, and CHD risk indicators in obese adults. Sixteen obese subjects (12 women/4 men) participated in a 10-week trial with three consecutive dietary intervention phases: (i) 2-week baseline control phase, (ii) 4-week ADF controlled feeding phase, and (iii) 4-week ADF self-selected feeding phase. After 8 weeks of treatment, body weight and waist circumference were reduced (P < 0.05) by 5.7 ± 0.9 kg, and 4.0 ± 0.9 cm, respectively. Fat mass decreased (P < 0.05) by 5.4 ± 0.8 kg, whereas fat-free mass did not change. Plasma adiponectin was augmented (P < 0.05) by 30% from baseline. Leptin and resistin concentrations were reduced (P < 0.05) by 21 and 23%, respectively, post treatment. Low-density lipoprotein cholesterol (LDL-C) and triacylglycerol concentrations were 25% and 32% lower (P < 0.05), respectively, after 8 weeks of ADF. High-density lipoprotein cholesterol (HDL-C), C-reactive protein, and homocysteine concentrations did not change. Decreases in LDL-C were related to increased adiponectin (r = -0.61, P = 0.01) and reduced waist circumference (r = 0.39, P = 0.04). Lower triacylglycerol concentrations were associated with augmented adiponectin (r = -0.39, P = 0.04) and reduced leptin concentrations (r = 0.45, P = 0.03) post-treatment. These findings suggest that adipose tissue parameters may play an important role in mediating the cardioprotective effects of ADF in obese humans.