Background: The plasminogen regulation system is critical in triggering proteolysis to cleave the extracellular matrix and basement membrane. The “uPA-uPAR” system is involved in extravascular fibrinolysis and is responsible for the formation of plasmin associated with invasion and metastasis. The purpose of the study was to analyze levels of factors of the plasminogen regulation system in the blood of patients with cutaneous melanoma (M) and chronic neurogenic pain (CNP). Methods: Blood levels of PAP, uPA, uPAR and PAI-1 were measured by ELISA in patients with Т_3-4N_xM₀ melanoma: 21 women with CNP (pelvic pain - 7, osteochondrosis – 14), mean age 67.2±2.7 years; 17 men with CNP (osteochondrosis), mean age 65.6±3.1 years. The control group included patients with melanoma similar in age, gender and disease stages without CNP. Results: Blood levels of PAP in women with M+CNP were twice higher than in patients with M without CNP, the levels in men with M+CNP did not change; uPA content increased in both women and men with M without CNP by 1.4 and 1.5 times, uPA activity was elevated only in women by 2.4 times, in men it was reduced by 2 times; uPAR was increased by 1.5 times in women and men compared to the values in both female and male patients with M without CNP. PAI-1 content in women and men with M+CNP was similar to control values, and its activity was increased in women by 1.5 times and decreased in men by 2.5 times. Conclusions: The study gives significant additional information on the effect of CNP on relationships in the plasminogen activation system in a combination of cutaneous melanoma and CNB showing marked gender differences. The results should be taken into account in the special treatment of patients with melanoma.