Many of the histopathologic criteria used to diagnose melanoma overlap with atypical but otherwise benign naevi such as dysplastic or Spitz naevi. Galectin-3 is a member of the galectin gene family and is expressed at elevated levels in a variety of neoplastic cell types. The aim of the present study was to investigate the diagnostic value of galectin-3 expression compared with homatropine methyle bromide-45(HMB-45) (one of the established and widely used immunohistochemical melanocytic markers) together with assessment of its prognostic value in melanoma lesions. This study was carried out on 21 cases of melanoma and 20 benign pigmented naevi. Galectin-3 was expressed in all the examined benign and malignant melanocytic lesions. The nucleocytoplasmic pattern of galectin-3 appeared in malignant cases only with 42.86% sensitivity, 100% specificity, and 70.73% accuracy. This pattern tended to be associated with thick melanoma (P = 0.08) and reduced survival (P = 0.22). The intensity of galectin-3 assessed by H-score was significantly of higher values in malignant lesions compared with benign lesions (P < 0.0001). The best cut-off value for discrimination between benign and malignant melanocytic lesions was 295 with 95% sensitivity, 70% specificity, and 83% accuracy. The diagnostic power of galectin-3 in distinguishing between benign and malignant melanocytic lesions relies on the pattern and the intensity of its expression. The nucleocytoplasmic pattern of galectin-3 expression carries greater probability of a malignant phenotype and a poor prognostic impact on patients' outcome.