Depression predicts increased risk of coronary artery disease and type 2 diabetes, and the metabolic syndrome (MS) is a putative link between depression and these diseases. There are no prospective studies of the effect of major depression on risk for the MS. This study examined the cross-sectional and longitudinal relationship of major depression with the MS, central adiposity, and insulin resistance (IR), over a period of 6 years. Data were drawn from the “Study of Women’s Health Across the Nation”, an ongoing, multi-site investigation of perimenopausal women. The sample included 421 women (34% Black), ages 42-52 (M = 45.6 + 2.5) from the ancillary Mental Health Study of the participants from the Pittsburgh site. Major depression diagnosis (lifetime history and current), other diagnoses (anxiety disorders, substance abuse/dependence) and antidepressant use were collected annually via the SCID-IV. The MS was measured at baseline and bi-annually thereafter; WC and IR were assessed annually. Health behaviors included smoking (annually), and physical activity and diet (baseline). Logistic regression and survival analyses examined the odds/risk of developing the MS over the course of the study in the full sample and in women free of the MS at baseline. Generalized Estimating Equations (GEE) examined the relationship between depression (time-varying) and the MS (time-varying) over the course of the study. Exploratory analyses were conducted to examine whether associations were independent of demographics, diabetes, and other diagnoses, and to examine the association of depression with WC. Baseline depression predicted marginally greater odds of having the MS over the course of the study (cumulative index) in the full sample, independent of covariates. Women with baseline depression showed a trend for increased risk of developing the MS; this effect was not significant. GEE analyses showed no significant concurrent associations between depression and the MS across time, suggesting that depression and the MS did not “track” together over time. Finally, baseline depression predicted greater WC at the final visit, although this was reduced after controlling for age and race. Findings suggest that major depression may be an important predictor of the prevalence and incidence of the MS in women.