Background: Hospital readmissions are costly to the healthcare system. Understanding patient factors associated with hospital readmission will facilitate targeting of interventions designed to reduce readmissions. Depressive symptoms are associated with poor patient outcomes and may impact hospital readmission. Objective: To investigate the association between depressive symptoms and 30-day unplanned hospital readmission. Non-adherence to discharge instructions was examined as a potential mediator of this association. Methods: We conducted a prospective cohort study of hospitalized patients ages 65 and older. Depressive symptoms were measured within 72 hours of admission to the University of Maryland Medical Center and defined as a score of greater than or equal to 6 on the Geriatric Depression Scale-15. Patients were then contacted three times post-hospital discharge to ascertain incident deaths, unplanned hospital readmissions, and adherence to discharge instructions. Results: 750 patients were enrolled in the study. Depressive symptoms were not associated with 30-day unplanned hospital readmission (RR 1.20; 95% CI 0.83, 1.72). Depressive symptoms were associated with non-adherence to the medication domain of the discharge instructions (OR 1.75; 95% CI 1.02, 2.99), but not with follow-up appointments (OR 1.25; 95% CI 0.62, 2.52), lifestyle recommendations (RR 0.94; 95% CI 0.75, 1.17), or overall non-adherence to the discharge instructions (COR 1.17; 95% CI 0.78, 1.75). Non-adherence to one or more domains of the discharge instructions at 5 days (OR 1.58; 95% CI 0.94, 2.65) or 15 days (OR 1.37; 95% CI 0.68, 2.74) post-hospital discharge was not significantly associated with 30-day unplanned hospital readmission. Because a significant association between depressive symptoms and 30-day unplanned hospital readmission was not observed, mediation was not assessed. Conclusions: In this sample of hospitalized adults aged 65 and older, neither depressive symptoms nor non-adherence to discharge instructions was significantly associated with 30-day unplanned hospital readmission. Hence, targeting interventions toward patients with depressive symptoms may not result in decreased hospital readmission. While depressive symptoms were associated with non-adherence to medication, other factors may play a greater role in predicting non-adherence to the discharge instructions. Further research is needed to identify predictors of non-adherence to the discharge instructions as well as to understand perceived barriers to non- adherence.