BACKGROUND The relation of physical activity (PA) and positive mood has been the focus of considerable research, which were primarily cross-sectional. This study was done to evaluate the relation between PA and high depressive symptoms across time and to examine whether being physically active attenuates the risk of depressive symptoms in midlife women. METHODS The present study is a longitudinal observational study on the menopausal transition in a multiethnic population. Ten years of data on 2891 women were analyzed. The participants were women from seven geographic areas nationwide, age 42-52 yr at baseline, still menstruating, and not using exogenous reproductive hormones. PA was measured with the Kaiser Permanente Physical Activity Scale. The main outcome measure, depressive symptoms, was assessed with the Center for Epidemiological Studies Depression Scale (CES-D), with primary outcome of CES-D score of 16 or higher. RESULTS In mixed effect logistic regression models adjusted for covariates, compared with inactivity, PA meeting PA guidelines (approximating public health guidelines) and PA below PA guidelines were each associated with lower risk of high depressive symptoms (CES-D score of 16 or higher) (odds ratio, 0.52; 95% confidence interval, 0.40-0.70; and odds ratio, 0.81; 95% confidence interval, 0.67-0.98, respectively] across 10 yr. Being married, Japanese and Hispanic ethnicity, current smoking, reporting very upsetting life events, using antidepressive medications, having hot flashes, and high body mass index were all positively associated with high depressive symptoms, whereas high social support was negatively associated. CONCLUSIONS Higher PA was associated with lower levels of depressive symptoms persistently over 10 yr, independent of potential confounders. Our findings suggest that reaching moderate-intensity PA levels during midlife may be protective against depressive symptoms.