Aim: To determine if weight loss differentially improves novel risk factors for cardiovascular disease in overweight women with and without polycystic ovary syndrome (PCOS). Methods: Age, weight and body mass index (BMI)- matched women with (n = 14) and without (n = 13) PCOS (age 34.3±5.7 years, weight 94.1±17.5 kg, BMI 35.1±5.2 kg/m2) followed an 8 week weight loss regime (5208.4±740.3 kJ/day). Primary outcome measures were the novel cardiovascular risk factors plasminogen-activator inhibitor-1 (PAI-1), inter-cellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM). Results: Equivalent reductions in weight (−4.2±4.0 kg) and waist circumference (−7.0±5.2 cm) occurred for women with and without PCOS. Compared to controls, women with PCOS had elevated PAI-1 (baseline 2.5±0.9 vs 1.8±0.7 ng/mL p = 0.034, post-weight loss 2.3±0.7 vs 1.7±0.6 ng/mL p = 0.047), ICAM (baseline 1.9±0.7 vs 1.5±0.6 ng/mL p = 0.047, post-weight loss 1.7±0.5 vs 1.4±0.4 ng/mL p = 0.032) and VCAM (post-weight loss 11.9±2.6 vs 9.5±1.7 ng/mL p = 0.009). Following weight loss there were equivalent reductions in ICAM (−0.2±0.3 ng/mL, p = 0.040) and VCAM (−0.8±1.8 ng/mL, p = 0.029) for women with and without PCOS. PAI-1 did not change with weight loss (p = 0.337) for either women with or without PCOS. Conclusions: We report for the first time that while modest weight loss equivalently reduces ICAM and VCAM in overweight women with and without PCOS, novel cardiovascular risk factors (PAI-1, ICAM and VCAM) remain elevated compared to controls following weight loss. Women with PCOS have significantly higher levels of inflammatory risk markers than weight and aged matched controls which can be partly ameliorated by weight loss.