To evaluate membrane biocompatibility, an open loop ex vivo model was designed simulating the hemodialysis procedure. Blood was withdrawn continuously from healthy nonuremic donors, heparinized, and pumped through a module containing the membrane to be studied. C3a generation in the module was determined at various time points comparing the cuprammonium cellulose (CC) membrane and four types of modified cellulose (MC) membrane, each with a different degree of hydroxyl (OH-) group substitution. In other studies, C3a generation in the ex vivo mode was compared with that during in vivo dialysis. In the ex vivo model, C3a generation with MC membranes was reduced by 70% compared with CC. However, within the MC group, the degree of C3a generation did not correlate with the degree of OH-group substitution. In vivo studies confirmed the reduced degree of C3a generation with the MC membrane compared with CC. Additionally, validation studies using the CC membrane showed excellent agreement between C3a generation during ex vivo perfusion and in vivo dialysis. The results suggest that a group of new MC membranes causes substantially less complement activation than the CC membrane but that the degree of complement activation with various subtypes of MC membranes is not related to the degree of OH-group substitution.