Objective To examine the effect of a combined exercise program on C1Q/tumor necrosis factor-related protein-3 (CTRP-3) and CTRP-5 levels, novel adiponectin paralogs that have been suggested as being links between metabolism and inflammation, and to evaluate gender differences and association with cardiometabolic risk factors in humans using a newly developed enzyme-linked immunosorbent assay. Methods This cross-sectional study explored the implications of CTRP-3 and CTRP-5 on cardiometabolic parameters in 453 non-diabetic Korean adults. In addition, we evaluated the impact of a three-month combined exercise program on CTRP-3 and CTRP-5 levels in 76 obese women. The exercise program consisted of 45 minutes of aerobic exercise at an intensity of 60-75% of the age-predicted maximum heart rate (300 kcal/session) and 20 minutes of resistance training (100 kcal/session) five times per week. Results Similar to adiponectin, circulating CTRP-3 concentrations showed sexual dimorphism, which is higher in women than in men. In a multiple stepwise regression analysis, CTRP-3 levels were independently associated with age, gender, triglycerides, LDL cholesterol, adiponectin and retinol binding protein 4 (RBP4) levels (R2 = 0.182). After three months of a combined exercise program, cardiometabolic risk factors including components of metabolic syndrome, insulin resistance and RBP4 levels decreased significantly. In particular, CTRP-3 levels decreased significantly (444.3 [373.8, 535.0] to 374.4 [297.2, 435.9], P <0.001), while levels of CTRP-5 were slightly increased (34.1 [28.6-44.3] to 38.4 [29.8-55.1], P = 0.048). Conclusion A three-month combined exercise program significantly decreased CTRP-3 levels and modestly increased CTRP-5 levels in obese Korean women.