The authors retrospectively tested the potential value of paraffin-reactive monoclonal antibodies (A103 against melan-A, T311 against tyrosinase) and antibody KBA62 as immunohistochemical markers for amelanotic metastatic melanomas. The study cases included 72 amelanotic metastases of known cutaneous melanomas, 59 poorly differentiated carcinomas, 73 sarcomas of varying histogenesis, 4 Leydig cell tumors, 10 high-grade lymphomas, and 6 plasmoblastic/anaplastic myelomas. The results were compared with immunostainings for S-100 protein and HMB-45. HMB-45, antimelan-A, and antityrosinase showed almost identical staining results, with a sensitivity of 0.85 for HMB-45 and of 0.86 for both antimelan-A and for antityrosinase. HMB-45 and antityrosinase both had a specificity of 1.00; the specificity of antimelan-A was 0.95 as a result of a positive reaction in three of three adrenocortical carcinomas and four of four Leydig cell tumors. KBA62 stainings resulted in a sensitivity of 0.86 for melanomas. A positive immunoreactivity of KBA62 alone had a specificity of only 0.83, but in conjunction with anti-S-100 protein (sensitivity, 1.00; specificity, 0.87) and anticytokeratin 8/18/19 (CK), a KBA62+/S-100+/CK- immunophenotype identified all except one of the melanoma cases that were negative for the three melanocyte-specific markers with a specificity of 0.99. In conclusion, we found comparable immunohistochemical sensitivities of HMB-45, antityrosinase, and antimelan-A for a highly specific identification of approximately 85% of amelanotic metastatic melanomas on paraffin sections. Melanomas that were negative for all of these specific markers might be sensitively and specifically detected with anti-S-100 protein and KBA62.