Depression is an important post-stroke sequela with negative impact on mortality, functional outcome and quality of life. Changes in cytokines have been hypothesized to be associated with the etiology of post-stroke depression (PSD). The altere dhypothalamic-pituitary-adrenal (HPA) functioning is associated with the onset of depression. The activity of HPA could induce the fluctuations of cortisol levels. In this study, we prospectively checked interleukin 6 (IL-6) and cortisol levels in patients with early ischemic stroke. It was hypothesized that early serum IL-6 and cortisol fluctuations in stroke patients were the predictions of PSD. Totally, 100 participants were selected from stroke inpatients consecutively admitted to the Department of Neurology, Tongji Hospital from July 2014 to December 2015. Fifty health people served as the controls. The serum of all the patients was collected at 8:00 am and 4:00 pm respectively one week after stroke. The serum of controls was collected only at 8:00 am. The levels of IL-6 were analyzed by enzyme-linked immunosorbent assay kit, and those of cortisol were detected by chemiluminescence immunoassay. On the 3rd week after stroke, the patients were enrolled to the PSD group and non-PSD group based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and The Hamilton Depression Rating Scale (HAMD-21, score > 7). The IL-6 level (13.24 +/- 2.89 ng/L) was elevated significantly in PSD groups as compared with that in non-PSD group and control group respectively (P < 0.05 for both), but there was no significant difference in the IL-6 level between non-PSD group and control group. The patients in both PSD group and non-PSD group had significantly elevated morning cortisol levels in comparison with those in the control group (P < 0.05; for PSD, non-PSD and control: 508.86 +/- 119.51, 420.83 +/- 70.04 and 340.40 +/- 76.30 nmol/L respectively). Moreover, afternoon cortisol levels in PSD group were significantly higher than those in non-PSD group, and the morning baseline cortisol levels in these two groups were similar (P > 0.05). It was suggested that PSD generally runs a chronic course and is related to a variety of adverse health outcomes including increased disability, morbidity and mortality. This study will help the screening of potential PSD in the early stage.