Natural killer (NK) cells are specific peripheral blood lymphocytes which are involved in the lysis of malignant and virally transformed cells. In a prospective study of eight hemodialysis patients, we investigated the effects of recurrent exposure to the cuprophane (CU) membrane on the number and functional ability of NK cells, against both their classical in vitro target, K562 cell line, as well as the beta 2m/HLA negative cells that emerge during dialysis with CU membrane. The percent of NK cells, defined by the CD56 epitope, increased from 27.7 +/- 7.9% of cells at baseline to 59.2 +/- 12.0% after two weeks of dialysis with new CU membrane (P < 0.01). The ability of these cells to lyse K562 cells decreased from 28.7 +/- 16.5% at baseline to 12.5 +/- 6.2% (P < 0.001) after two weeks of dialysis with CU membrane, while their cytotoxicity against beta 2m negative cells increased during the same period from 32.5 +/- 12.4% to 61.3 +/- 23.7% (P < 0.001). These results are consistent with the observation that the cytolytic ability of NK cells is inversely related to target cell expression of HLA antigens and beta 2m expression on cell surfaces. In addition, the results of these studies confirm in vitro observations of the decrease in cytolytic activity of the NK cells when exposed to the CU membrane, and may explain the emergence of these beta 2m/HLA negative cells during dialysis with CU membrane. It is possible that these observations may also have a clinical relevance to the immune defects and increased incidence of malignancy in uremia.