Background: Physical activity is associated with a lower prevalence of depressive symptoms in cardiac patients. However, the benefits of physical activity on depression perioperatively are unknown. We sought to identify independent parameters associated with depression in patients undergoing cardiac surgery. Methods: Patients awaiting nonemergent cardiac surgery (n = 436) completed the Patient Health Questionnaire-9 (PHQ-9) to quantify depression (PHQ-9 score > 9). Physical activity was assessed with the International Physical Activity Questionnaire (IPAQ-short) and accelerometry. Data collection occurred preoperatively (Q1, n = 436), at hospital discharge (Q2, n - 374), at 3 months (Q3, n - 318), and at 6 months (Q4, n = 342) postoperatively. Patients were categorized as "depression naive", "at risk" or "depressed" preoperatively. Physical inactivity was defined as < 600 metabolic equivalent min/wk. Independent perioperative variables associated with depression were identified with univariate and multivariate logistic regression. Results: Depression prevalence from Q1-Q4 was 23%, 37%, 21%, and 23%, respectively. Independent associations with depression were preoperative left ventricular ejection fraction < 50% (Q1, P < 0.05), physical inactivity (Q1, P < 0.05), baseline "at-risk" (Q2, P < 0.05), and baseline "depressed" groups (Q2-Q4, P < 0.05), hospital stay > 7 days (Q2, P < 0.05), postoperative stressful event (Q3 and Q4, P < 0.05), and cardiopulmonary bypass time > 120 minutes (Q4, P = 0.05). Newly depressed patients 6 months postoperatively reported lower IPAQ-short physical activity than depression-free patients (median change, -40 min/wk (interquartile range [IQR], -495 to +255) vs +213 min/wk (IQR, +150 to +830; P < 0.05). Conclusions: Up to 40% of patients are depressed after cardiac surgery. Preoperative depression and postoperative stressful events were the strongest independent associations postoperatively. Physical inactivity was associated with preoperative depression and new depression 6 months postoperatively.