The preventive effects of various doses of the immunomodulator P40 on the experimental E. coli infection of the upper and lower urinary tract have been investigated in the rat. Under our experimental conditions, P40 only weakly influenced the bacteriological picture of the infection in rats infected by the upper route. However, the development of nephropathia might be decreased. By contrast, P40 was found to prevent the development of infection in two thirds of cases infected by the lower route. The preventive effect of P40 on infections of the lower urinary tract seems to be mostly medicated by the stimulation of phagocytosis, although both humoral and cellular immunity are likely to be involved. In contrast, the defense is most probably to be ascribed to cellular immunity in infections of the upper urinary tract. For the future, conditions will have to be specified which enable P40 to express predominantly its stimulating effect on cellular immunity. Furthermore, the choice of the minimum active dose together with its fractionated administration will prevent side-effects (prostatitis) while resulting in equally pronounced protective action. Since P40 has already successfully been used in man for the treatment of both infectious and tumoral processes, it could as well be used for the prevention of relapses in recurrent urinary infections.