Immunohistochemical staining with monoclonal antibodies showed marked variations in the percentage of melanoma cells stained by anti-HLA Class I and anti-HLA Class II monoclonal antibodies among 48 locoregional metastases removed from 39 patients with malignant melanoma. On the other hand there was limited variation in the percentage of melanoma cells stained by anti-HLA antibodies in autologous locoregional metastases removed from 8 of 9 patients. In the remaining patient marked differences were found in the percentage of melanoma cells stained by anti-HLA Class I antibodies in the two parts of the lymph node metastasis analyzed. Therefore this patient was not included in additional analyses to correlate the level of expression of HLA antigens with the clinical course of the disease. In all the lesions tested the percentage of melanoma cells stained by anti-HLA Class II antibodies was lower than or equal to but never higher than that stained by anti-HLA Class I antibodies. According to the level of expression of HLA Class I and Class II antigens the 38 patients could be divided into three groups: Pattern A included lesions with more than 50% of tumor cells stained by anti-HLA Class I antibodies (mean, 86.1; median, 85) and 50% or less by anti-HLA Class II antibodies (mean, 10.5; median, 5); Pattern B included lesions with 50% or less tumor cells stained by anti-HLA Class I antibodies (mean, 14.9; median, 5) and by anti-HLA Class II antibodies (mean, 4.1; median, 1); Pattern C included lesions with more than 50% tumor cells stained by anti-HLA Class I antibodies (mean, 88.8; median, 92) and by anti-HLA Class II antibodies (mean, 70.0; median, 70). The survival of 21 patients with Pattern A was significantly longer than those of 13 and 4 patients with Patterns B and C, respectively. No difference in the survival of patients in the latter two groups was found. These results suggest that HLA antigens play a role in the biology of melanoma and that analysis of the level of HLA antigens in locoregional metastases of patients with melanoma may provide clinically useful information.