Correlated analysis of the H-ras oncogenes product (p21) and of nuclear DNA content was performed by flow cytometry (FCM) in patients with DNA-aneuploid multiple myeloma (MM). Bone marrow cells from normal donors and MM patients in remission served as controls. Seventy-four percent of 23 patients with active MM had higher p21 fluorescence in aneuploid tumor cells than were observed in normal donor or myeloma remission bone marrows; 39% of the 23 patients also showed high H-ras p21 expression in diploid cells. There was an inverse relationship between p21 levels and the presence of trisomy 11; especially high p21 levels were noted in patient without trisomy 11. The frequent elevation of p21 protein in aneuploid plasma cells suggests the involvement of the H-ras oncogene in the pathophysiology of MM, which is further supported by a shorter survival among patients with high p21 levels.