Background: Post-stroke depression (PSD) is the most common psychological consequence of stroke. Increased inflammatory markers resulting from ischemic stroke may played an important role in the pathogenesis of depressive symptomology. The present study was conducted to further elucidate the relationship between stroke severity, systemic low-grade inflammation and chronic phase post-stroke depressive symptomology (CP-PSDS). Methods: A total of 897 stroke patients were consecutively recruited in this multicenter prospective cohort study and followed up for 1 year. The analytical sample consisted of 436 patients with ischemic stroke (23.4% female, median age = 57 years) from this cohort. Serum concentrations of inflammatory markers were measured in all 436 patients with ischemic stroke, from fasting morning venous blood samples on admission. Stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) on admission and post-stroke depressive symptomology (PSDS) was evaluated by 17-item Hamilton Rating Scale for Depression (HRSD). Results: In the fully adjusted models, we observed that 1) NIHSS (Model 2: beta = 0.200, 95%CI, 0.057 similar to 0.332), fibrinogen (Model 2: beta = 0.828, 95%CI, 0.269 similar to 1.435), white blood cell counts (WBC, model 2: beta = 0.354, 95% CI, 0.122 similar to 0.577) and neutrophil counts (Model 2: beta = 0.401, 95%CI, 0.126 similar to 0.655) can independently predict the CP-PSDS after ischemic stroke onset; 2) fibrinogen (Indirect effect = 0.027, 95%CI, 0.007 similar to 0.063, 13.4% mediated), WBC (Indirect effect = 0.024, 95%CI, 0.005 similar to 0.058, 11.8% mediated) and neutrophil counts (Indirect effect = 0.030, 95%CI, 0.006 similar to 0.069, 14.8% mediated) could partially mediate the association between stroke severity and CP-PSDS, and 3) stroke severity might cause CP-PSDS partly through the chain-mediating role of both fibrinogen and neutrophil counts (chain mediated effect = 0.003, 95%CI, 0.000 similar to 0.011, p = 0.025, 1.6% mediated). Conclusions: Findings revealed that fibrinogen, WBC and neutrophil counts may be independent predictors of CP-PSDS and partial mediators of the relationship between stroke severity and CP-PSDS among patients with ischemic stroke. In addition, the chain mediating effect of fibrinogen and neutrophil counts might play an important role in the occurrence of CP-PSDS. However, no inflammatory markers were associated with CP-PSDS in females.