Our study aimed to explore the association between serum C-reactive protein (CRP) and post-stroke depressive symptoms. We prospectively recruited 572 patients with ischemic stroke or transient ischemic attack in whom serum CRP level was measured within 48 h after stroke onset. Depressive symptoms were assessed at day 8 and 3 months after stroke in 405 and 306 patients, respectively. Patients with greater depressive symptoms at day 8 and patients with greater depressive symptoms 3 months after stroke had higher CRP level (median: 7.9 vs 4.3 mg/L, P < 0.01 and 6.7 vs 3.4 mg/L, P = 0.01, respectively). In the univariate analysis, CRP > 9.2 mg/L was associated with depressive symptoms at day 8 (OR: 2.06, 95%CI: 1.30-3.28, P < 0.01) and CRP > 4.3 mg/L was associated with depressive symptoms 3 months after stroke (OR: 1.79, 95%CI: 1.06-3.02, P = 0.03). In the multivariate analysis, higher CRP level was related to depressive symptoms at day 8 (OR: 2.23, 95%CI: 1.28-3.90, P < 0.01), but not depressive symptoms 3 months after stroke (OR: 1.13, 95%CI: 0.59-2.17, P = 0.71). In conclusion, higher levels of CRP are associated with greater depressive symptoms at day 8 after stroke, but their effects on depressive symptoms 3 months after stroke are less significant.