Both low urinary pH and radiocontrast agents may intensify myeloma nephrotoxicity. To study the effects of these factors, we determined inulin clearances (C(In)) before and after infusions of human Bence Jones protein (BJP) in male Sprague-Dawley rats in a dose previously shown to be nephrotoxic. Rats that drank 0.15 M NaHCO3 for 48 hr before study had no change in C(In) (+3 ± 20%) after BJP unlike those that drank 0.15 M NH4Cl (-33 ± 14%, P < 0.05); urinary pH differed (7.6 ± 0.1 vs. 6.2± 0.1, P < 0.05), but urinary flow rates did not. The acidifying regimen was used in all subsequent groups. Infusion of fiatrizoate (DTZ) after BJP produced a further decrease in C(In) (-85 ± 8%, P < 0.05). In contrast, infusion of albumin, which raised plasma protein concentration to that seen in BJP-infused rats, did not change C(In) (+39 ± 17%). Infusion of beta-lactoglobulin also led to a greater decrease in C(In) after DTZ (-35 ± 9 vs. -67 ± 8%, P < 0.05), but myoglobin did not (-58 ± 7 vs. -54 ± 12%). Urinary pH and flow rate did not differ between any DTZ-infused group and its appropriate control. These data suggest that aciduria independent of urinary flow rate increases the nephrotoxicity of BJP. In this setting, DTZ further intensifies the nephrotoxicity of BJP as well as some but not all filterable proteins.