We have found a human serum, E27, obtained from a multiply transfused patient with systemic lupus erythematosus, which immunoprecipitates the lymphocyte function associated antigen-1 (LFA-1). The immunoprecipitated molecules were identified as the LFA-1 alpha and beta chains by their comigration on SDS-PAGE, two-dimensional SDS-PAGE, and by sequential clearance experiments. Serum E27 did not immunoprecipitate LFA-1 from autologous cells, though LFA-1 molecules were present. In contrast, serum E27 immunoprecipitated LFA-1 from most but not all normal donor lymphocytes. Thus, serum E27 defines two serological phenotypes of LFA-1. 95% of normal individuals tested exhibited the LFA-1 phenotype precipitated by serum E27. Serum E27 appears to be directed at determinants of the LFA-1 alpha-chain and not the beta-chain since it immunoprecipitated LFA-1 molecules but not the Mac-1 molecules. Additional evidence for the alpha chain specificity was provided by immunoprecipitation of mouse-human heterohybridoma cells. LFA-1 was immunoprecipitated by serum E27 from mouse-human heterohybridoma cells expressing the human alpha-chain, not from a hybrid cell line expressing the human beta-chain. Together these findings demonstrate an antigenic polymorphism of the human LFA-1 alpha-chain molecule.