Immunochemical studies have shown that the monoclonal antibody (MoAb) CL203.4, elicited with immune interferon treated cultured human melanoma cells Colo 38, recognizes intercellular adhesion molecule 1 (ICAM-1). The determinant defined by MoAb CL203.4 is distinct and spatially distant from that defined by anti-ICAM-1 MoAb RR1/1, which had been elicited with Epstein-Barr virus-transformed B-lymphocytes from a lymphocyte function associated antigen 1 deficient patient. Immunohistochemical testing with MoAb CL203.4 of surgically removed lesions of melanocyte origin has shown a markedly lower reactivity with benign than with malignant lesions. Among the latter, a higher percentage of metastatic than of primary lesions was stained by MoAb CL203.4. The higher expression of ICAM-1 in metastases than in primary lesions is unique to melanoma, since no difference was found in its distribution in primary and metastatic lesions of a variety of malignancies of different embryological origin. Reactivity with MoAb CL203.4 of primary lesions removed from patients with stage I melanoma showed a highly significant correlation with the lesion thickness and with the clinical course of the disease. The disease free interval in patients without detectable reactivity of their primary lesion with MoAb CL203.4 was significantly (P = 0.004) longer than that of patients whose primary lesion was stained with MoAb CL203.4. These results suggest that ICAM-1 may be a useful marker in the analysis of the molecular mechanism underlying the association between lesion thickness and clinical course of the disease.