Unilateral nephrectomy (UNX) induces a dramatic change in single-kidney structure and function. Therefore, the effects of nephrotoxins may be altered. To evaluate this possibility, mercuric chloride (2 mg/kg, sc) was given to male, Sprague-Dawley rats 2 days following either UNX or sham surgery. Nonoliguric acute renal failure developed and was qualitatively similar in both groups. Glomerular filtration rate (GFR) reached a nadir on Day 2 and was reduced to a greater extent in the UNX group. Furthermore, recovery of GFR was slower and occurred to a lesser extent by Day 10 in the animals subjected to UNX. Evidence of significant tubular dysfunction was present during the acute phase in both groups, as reflected by changes in the fractional excretion of sodium or lysozyme. Persistent tubular dysfunction was noted on Day 10 in both the sham and UNX groups, but the degree of dysfunction was greater in the UNX animals. The in vitro uptake of organic ions by renal cortical slices was reduced 24 hr following the injection of mercuric chloride although no difference was seen between the experimental groups. Mercury content within renal cortex was not increased in the UNX group at 1 or 3 hr but was higher 24 hr postinjection. Total urinary mercury excretion during the first day was not altered by UNX although single-kidney excretion was increased dramatically. These studies suggest that rats are more susceptible to mercuric chloride-induced nephrotoxicity 2 days following UNX. Although the mechanism(s) of this enhanced injury remains unclear, it does not appear to be completely related to an increase in renal cortical mercury content.