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Background: OPN3 upregulation associated with metastasis was recently described in two subtypes of lung cancers. And OPN3 identified in light‐independent functions in epidermal melanocytes has already shown promise. However, in malignant melanocytic tissues, the expression and characterization of OPN3 remain uncharacterized. Objectives: We investigated the clinico‐histopathologic features in relation to OPN3 expression of acral lentiginous melanoma (ALM), which is a rare cutaneous melanoma subtype and not associated with prior sunlight exposure. Methods: In all, 84 samples of junctional melanocytic nevi (JMN, n = 12), primary ALMs (n = 39) and inguinal lymph node metastasis (ILNM, n = 23) from ALMs were evaluated for the immunohistochemical expression of OPN3. OPN3 messenger RNA and protein level were further determined in melanocytic tumors using quantitative real‐time PCR, multiimmunofluorescence and Western blot assays. We also estimated the associations OPN3 expression between clinicopathological features and prognosis. Results: ILNMs, in contrast to JMN and ALMs, had higher OPN3 expression scores (p <.001) by immunohistochemistry analysis. High OPN3 score was associated with presence of ulceration, increased Breslow depth and Clark level (p =.025, p =.042, and p =.012, respectively). Furthermore, a remarkable difference (p =.037) of patient overall survival was found when comparing the OPN3 expression of immunohistochemical score between equal to or larger than 100 and below 100 groups. Also, Cox regression models showed that high OPN3 scores were associated with worse melanoma survival. Conclusion: High OPN3 expression is significantly associated with ALMs and metastatic phenotype as well as a poor prognosis. [ABSTRACT FROM AUTHOR]