Background: The hypothalamic-pituitary-adrenal axis (HPA) maintains homeostasis and the body's response to any stressful effects. Skin cells are capable of local synthesis of steroid, thyroid and regulatory hormones, which makes the skin an analogue of HPA. The purpose of the study was to reveal the effects of transplantable В16/F10 melanoma on central HPA axis and its skin analogue in mice taking into account the gender of animals. Methods: The study included 40 female and 40 male С57BL/6 mice with transplantable В16/F10 melanoma in weeks 1, 2, 3 and 4 of its growth. Hormonal levels were determined by ELISA and RIA in homogenates of hypothalamus, pituitary, adrenal and tumor and in the intact skin. Results: During the melanoma growth, male mice demonstrated an increase in CRF in the hypothalamus, the ACTH decrease in the pituitary and a sharp increase of cortisol in the adrenal glands. At the same time, levels of CRF, ACTH and cortisol increased from the second week in tumor which probably promoted autocrine/paracrine regulation of proliferation processes in the tumor tissue. The melanoma growth in female mice was associated with an increase in CRF in the hypothalamus, with ACTH increase starting from week 3 and a gradual increase in cortisol in the adrenal glands starting from week 2. CRF and ACTH levels increased in melanoma as well, but skin levels of cortisol decreased. Conclusions: In the dynamics of the melanoma growth, male mice demonstrated the loss of sensitivity in the pituitary component of the HPA axis to the stimulating effect of the hypothalamus; in females, regulatory connections were not impaired. In males, the skin analogue of the HPA axis was activated, which was indicated by an increase in the level of regulatory hormones in growing melanoma and surrounding tissues.