Background: There are limited data concerning the relationships between changes in adipocytokines and cardiovascular disease (CVD) risk factors. Objective: To examine the longitudinal associations between leptin, adiponectin, resistin and ghrelin levels and CVD risk factor levels in women at midlife. Design: Prospective, observational study. Subjects and measurements: Leptin, adiponectin, resistin, ghrelin levels and CVD risk factors were measured in specimens collected from 40 women at 3 points in time corresponding to the pre-, peri-and postmenopause stages of their natural menopause transition. Results: In longitudinal analyses adjusted for CVD risk factors and leptin at the previous menopausal stage, aging, education, smoking and physical activity, greater increases in leptin over the menopause transition were associated with greater decreases in high-density lipoprotein cholesterol (HDL-c) and greater increases in diastolic blood pressure, glucose, insulin and insulin resistance (all Po0.05). Larger decreases in adiponectin over the menopause transition were associated with greater increases in systolic blood pressure, insulin and insulin resistance and with greater decreases in HDL-c. Greater increases in ghrelin levels over the menopausal transition were associated with greater low-density lipoprotein cholesterol increases (P ¼ 0.014). Resistin was not associated with CVD risk factor changes. Conclusion: There were significant adverse associations of adipocytokines and ghrelin with multiple CVD risk factor changes in women across midlife. Given that this time period is dynamic for CVD risk, these data underscore the need for additional prospective studies.