In yeast, RAD52 has been shown to be essential for homologous recombination of DNA and to be involved in the repair of double-stranded DNA breaks. Recently, the human homologue of yeast RAD52, a 418-amino-acid protein, has been identified. In this study, we report three different isoforms of human RAD52 isolated from brain and testis cDNA libraries. cDNAs of these isoforms contain distinct insertions and encode truncated proteins due to translational frame-shifts. The three isoforms consist of 226-, 139-, and 118-amino-acid residues, and are designated as RAD52beta, gamma, and delta, respectively. The original RAD52 is termed as RAD52alpha in this paper. Messages of these isoforms have been detected in various human tissues. We found that the RAD52 isoforms were unable to interact with RAD52alpha because of partial defect of the self-interaction domain. Furthermore, like RAD52alpha, the isoforms have been shown to bind to both single-stranded and double-stranded DNA. These results suggest that RAD52beta, gamma, and delta might affect RAD52alpha function through their DNA-binding property and their inability to bind to RAD52alpha. Thus, these isoforms might act as dominant negative mutants or negative regulators of RAD52alpha.