Experimental pyelonephritis was produced by either retrograde or direct infection of rat kidneys by Escherichia coli 078. Combined antibiotic therapy with amoxycillin and gentamicin, commenced within 23 h of direct infection, prevented acute suppuration and subsequent scarring. The same antibiotic combination commenced 24 h after both retrograde and direct infection did not significantly reduce acute suppuration but did reduce scarring. Treatment begun later than 24 h after infection had no effect on the outcome of pyelonephritis induced by either route. Significantly lower peak levels of serum antibody to the·antigen of E. coli O78 were obtained in rats treated at 24 h after retrograde pyelonephritis than in those in which treatment was started later. Kidney scarring could not be prevented if antibiotic therapy was commenced after the appearance of mononuclear cells in the inflammatory lesion.