The serum level of lactate dehydrogenase (LDH) is an important predictor of prognosis and treatment response in melanoma patients. It is unknown whether the expression of LDH-5 in tissue sections also has prognostic significance and whether it is related to the expression of the anti-apoptotic proteins, Bcl-2, Bcl-XL and Mcl-1, and endoplasmic reticulum stress protein glucose-regulated protein 78 (GRP78). Identification of an association between LDH-5 expression and anti-apoptotic proteins may have important therapeutic implications for melanoma patients. Sections from 159 pigmented lesions, including nevi and melanoma at different stages of progression were studied by immunohistochemistry. Correlation of LDH-5 expression with clinicopathological factors and with the expression of Bcl-2, Bcl-XL, Mcl-1 and GRP78 was examined. LDH-5 was detected at low levels in 6 of 10 compound nevi (60%) and 6 of 10 dysplastic nevi (60%). The percentage of positive cases was greater in thin (≤1.0mm) (74%) and thick primary melanoma (>1.0mm) (95%) and in metastatic melanoma in the skin (100%) and lymph node (81%). The immunoreactive score was highly related to progression of melanoma (P<0.0001). LDH5 expression was positively associated with increasing tumor thickness (P=0.02) and dermal tumor mitotic rate (P=0.02). LDH-5 above the median immunoreactive score was associated with reduced disease-free survival and overall survival (P<0.02). LDH-5 expression was negatively associated with Bcl-2 expression. In contrast, LDH-5 expression was strongly associated with Bcl-XL and Mcl-1 expression and also positively associated with GRP78 expression (P<0.0001). The low Bcl-2 expression in melanomas with high LDH-5 expression provides an explanation for the poor response of patients with high serum LDH levels to treatment with the Bcl-2 antisense drug ‘Genasense’. The strong correlation of LDH-5 expression with Mcl-1 expression suggests that treatment strategies inhibiting the activity of Mcl-1 in melanoma patients should be investigated.