Objective To study the effect of atrial natriuretic peptide (ANP) deletion on melanoma growth. Methods A subcutaneous xenotransplanted melanoma model was established in ANP knockout mice and C57BL/6J mice. The tumor volume was measured at the sixth day after establishment of the subcutaneous transplantation. Tumor cell proliferation and tumor-induced angiogenesis were detected by immunohistochemical staining. Results The volume and weight of xenotransplanted melanoma were significantly decreased in the ANP knockout mice compared with those in the C57BL/6J mice. The proliferative tumor cells and microvessel density were significantly decreased in the tumor tissues of ANP knockout mice compared with those in the C57BL/6J mice. Conclusions ANP deletion significantly suppresses xenotransplanted melanoma growth through inhibiting the tumor cell proliferation and angiogenesis.