Previous studies have demonstrated a high level of heterogeneity associated with human renal cell carcinoma (RCC). In order to probe further this heterogeneity monoclonal antibodies were produced after immunization of mice with extracts of fresh renal tumor specimens. Four monoclonal antibodies designated LD-M1, LD-M2, LD-M5, and LD-M8 were generated and characterized immunohistochemically on a panel of tissue sections. The LD monoclonal antibodies strongly stained paraffin sections obtained from 77 to 100% of cases of RCC. Testing the sections with a library of polyclonal and monoclonal antibodies resulted in the definition of the following immunohistochemical phenotype of RCC: positive with the LD-M1, LD-M2, Ld-M5, LD-M8, Uro-2, Uro-7, Uro-10, cytokeratin, keratin, TPA, vimentin, Fx1A, retinol binding protein, CALLA and B72 antibodies; negative with the prekeratin, desmin, A5.48, uromucoid, and CEA antibodies. The pattern of immunohistochemical activity indicates that some RCC tumor cells contain epitopes associated with distal tubules in addition to previously documented antigens present in proximal tubules. Using a solid-phase competition radioimmunoassay it was observed that the serum of patients with renal cell carcinoma contains a circulating LD-M5-reactive tumor-associated antigen.