Aims: To investigate the correlation between the incidence of post-stroke depression (PSD) and the levels of substance P (SP) in the plasma and cerebrospinal fluid (CSF). Methods: Ninety-one stroke patients were divided into PSD (n = 46) and post-stroke (without depression) groups (n = 45). PSD must have occurred 2-4 weeks after the onset of the stroke and was determined by the Hamilton Rating Scale for Depression (HAMD). In addition, the subjects were divided into anterior (n = 67) and posterior circulation stroke groups (n = 24) based on the location of the focus as determined by computed tomography. All recruited patients were graded by the National Institutes of Health Stroke Scale (NIHSS). Results: The results included the following findings: (i) the level of plasma SP in the PSD group (58.47 +/- 14.39) was higher than that of the PS group (36.98 +/- 9.49; P = 0.000), while the level of CSF SP in the PSD group (72.13 +/- 13.06) was higher than that of the post-stroke group (37.30 +/- 12.57; P = 0.03); (ii) the level of plasma SP was positively correlated with the HAMD and NIHSS score; (iii) the level of plasma SP (38.45 +/- 12.23), the HAMD score (9.08 +/- 8.72), and the NIHSS score (3.25 +/- 1.90) of the anterior stroke group (51.21 +/- 16.27, 17.46 +/- 15.96, and 6.91 +/- 3.30, respectively) were higher than those of the posterior stroke group (38.45 +/- 12.23, 9.08 +/- 8.7, and 3.25 +/- 1.90, respectively; P = 0.017, P = 0.001, and P = 0.000, respectively). Conclusions: SP in the plasma and CSF of patients exhibited a close correlation with neural damage and the incidence of PSD. This study also suggested that anterior hemispheric strokes may play a significant role in development of PSD.