Cuprophane hemodialysis is associated with an early fall of leukocyte counts and an intradialytic rise in serum β2-microglobulin (β2M), in contrast to dialysis with more compatible dialyzers. It has been suggested that these two phenomena may be related. This study sets out to verify this hypothesis by comparing the evolution of leukocyte counts with that of β2M: (1) during dialysis with 5 dialyzer types with different pore size and/or leukocyte biocompatibility; (2) during first use and reuse of 3 dialyzer types, and (3) during sequential ultrafiltration and dialysis with cuprophane. In first-use dialyses, no relation could be found between changes in leukocyte counts and the evolution of β2M levels. Reuse of cuprophane and saponified cellulose ester resulted in a marked attenuation of the intradialytic fall in leukocyte counts after 15 min (change in white blood cell count: -72 and -17% for first-use and third-reuse cuprophane, -72 and -23% for saponified cellulose, respectively), but had no influence on the increase in β2M. Correlation studies of these data revealed that the intradialytic evolution of β2M was related to membrane pore size and, for membranes with a small pore size, to the intradialytic fluid losses: first-use cuprophane (p < 0.05), saponified cellulose ester (p < 0.001) and hemophane (p < 0.01), and pooled first-use and reuse cuprophane and saponified cellulose ester (p < 0.001). Cuprophane dialysis without ultrafiltration (dialysate Na+: 138 and 132 mEq/1) caused a fall in leukocytes, but induced no rise in β2M. Ultrafiltration with cuprophane either preceding or following dialysis consistently caused a rise in serum β2M, although a fall in leukocyte counts only occurred in the first case. Our data point away from a relationship between membrane biocompatibility, expressed as changes in leukocyte counts, and β2M concentration during hemodialysis. The major contributing factors appear to be dialytic fluid losses and membrane pore size.