Objective To investigate serum p75 neurotrophin receptor-extracellular domain (p75NTR-ECD) level in patients with chronic cerebral hypoperfusion-vascular cognitive impairment (CCH-VCI) and its relationship with tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6. Methods The clinical data of patients with CCH-VCI (n=34) were collected from Changhai Hospital, Naval Medical University (Second Military Medical University) from Aug. to Dec. 2018. Enzyme linked immunosorbent assay was applied for detection of serum levels of p75NTR-ECD, TNF-α, IL-1β and IL-6; and the results were then compared with those of ischemic stroke participants (n=34) and healthy controls (n=36), who were all in the same age range. Spearman correlation analysis was used to analyze the relationship between serum p75NTR-ECD level and the above-mentioned inflammatory factors in CCH-VCI patients. Results The serum p75NTR-ECD level in the CCH-VCI group was significantly higher than those in the healthy control group and the ischemic stroke group (544.36[440.88, 628.50] pg/mL vs 276.49[262.59, 313.87] pg/mL and 366.87[337.09, 450.43] pg/mL, U=87.500 and 335.500, both P<0.05). The serum levels of TNF-α, IL-1β and IL-6 were 196.02 (141.20, 280.35) pg/mL, 68.23 (60.79, 91.94) pg/mL and 51.04 (40.24, 65.26) pg/mL in the CCH-VCI group, respectively, and 218.67 (143.76, 281.28) pg/mL, 76.87 (59.10, 99.91) pg/mL and 64.45 (43.13, 86.76) pg/mL in the ischemic stroke group, respectively, which were all significantly higher than those in the healthy control group (73.71[56.94, 79.81] pg/mL, 42.98[34.52, 51.34] pg/mL and 14.97[11.76, 21.19] pg/mL, respectively; U=31.000 and 4.000, 106.000 and 132.000, and 48.000 and 13.000; all P<0.05). Serum p75NTR-ECD level in the CCH-VCI patients was correlated with TNF-α level (r=0.391, P=0.022), but not with IL-1β or IL-6 levels (r=0.032 and 0.164, P=0.855 and 0.355). Conclusion Serum p75NTR level may be related to inflammatory factors (TNF-α) after chronic cerebral hypoperfusion, and they may jointly participate in the pathogenesis of CCH-VCI.