In order to elucidate the mechanism of peritoneal dialysis fluid inhibition of cell functions, laboratory-prepared fluids were used to investigate the specific influences of low pH and high lactate concentration on neutrophil viability, phagocytosis, respiratory burst activation and leukotriene B4 (LTB4) generation. In the absence of any reduction of viability, respiratory burst activation, stimulated by serum-treated zymosan (STZ), was significantly inhibited by fluids of low pH containing high concentrations of sodium lactate. Neither low pH nor lactate concentration alone, however, caused significant suppression of this parameter of cell activation. Under the same conditions, the phagocytosis of STZ was partially inhibited in a lactate- and pH-dependent manner. In contrast, the generation of LTB4 in response to STZ was unaffected by pH and lactate concentration. The incubation of polymorphonuclear leukocytes (PMN) in fluids containing 35 mM lactate at pH 5.2 resulted in an immediate and profound lowering in intracellular pH ([pH]i) which was not observed in lactate-containing fluids at neutral pH or at low pH in the absence of lactate. We postulate that the critical lowering of [pH]i in PMN, caused by the combination of high lactate concentration and low pH of the dialysis fluids, is responsible for the observed inhibition of respiratory burst activation. It is also possible that under these conditions, the lactate ion acts as a proton carrier across the cell membrane following the [H+] gradient. The time course of this [pH]i change suggests that host defence mechanisms may be impaired following short-time exposure to unused dialysis fluid prior to its equilibration in vivo.