Background: Depression has been associated with elevated white blood cell (WBC) count - indicative of systemic inflammation - in cross-sectional studies, but no longitudinal study has evaluated whether depressive symptoms predict subsequent WBC count or vice versa. We sought to evaluate the bidirectional association between depressive symptoms and WBC count in patients with coronary heart disease (CHD). Methods: Depressive symptoms were assessed at baseline and annually during 5 consecutive years of follow-up in 667 outpatients with stable CHD from the Heart and Soul Study. The presence of significant depressive symptoms was defined as a score of ≥10 on the Patient Health Questionnaire (PHQ-9) at one or more assessments. WBC count was measured in blood samples collected at baseline and after 5 years of follow-up. Results: Of the 667 participants, 443 (66%) had no depressive symptoms (PHQ-9<10), 86 (13%) had depressive symptoms (PHQ-9≥10) at 1 assessment, and 138 (21%) had depressive symptoms at 2 or more annual assessments. Across the three groups, participants with recurrent depressive symptoms had higher WBC levels after 5 years of follow-up (p<.001). This relationship was essentially unchanged after adjustment for demographics, traditional cardiovascular risk factors, cardiac disease severity, inflammatory cytokine levels, and health behaviors (p=.009). Baseline WBC count was not associated with subsequent depressive symptoms (p=.18). Conclusions: Depressive symptoms independently predicted higher subsequent WBC count in patients with stable CHD, but baseline WBC count did not predict subsequent depressive symptoms. These findings support a unidirectional relationship in which depression is a risk-factor for inflammation. © 2012 Elsevier Ltd.