The retinoic acid-related orphan receptors (RORs) regulate several physiological and pathological processes, including immune functions, development and cancer. To study the potential role of RORs in melanoma progression, we analysed RORβ and RORη expression in nevi and primary melanomas and non-lesional skin and metastases in relation to melanoma clinico-pathomorphological features. The expression of RORβ and RORη was lower in melanomas than in nevi and decreased during melanoma progression, with lowest levels found in primary melanomas at stages III and IV and in melanoma metastases. Their expression correlated with pathomorphological pTNM parameters being low in aggressive tumors and being high in tumors showing histological markers of good prognosis. Higher nuclear levels of RORβ and RORη and of cytoplasmic RORη correlated with significantly longer overall and disease free survival time. Highly pigmented melanomas showed significantly lower level of nuclear RORs. This study shows that human melanoma development and aggressiveness is associated with decreased expression of RORβ and RORη, suggesting that RORs could be important in melanoma progression and host responses against the tumor. Furthermore, it suggests that RORβ and RORη might constitute a novel druggable target in anti-melanoma management using tumor suppressor gene therapy restoring their normal functions.