Histomonosis (blackhead disease or infectious enterohepatitis) caused by the extracellular protozoon parasite Histomonas meleagridis is an important disease of turkeys and a threat to the poultry industry. Due to recent legislation on drug restrictions, research to find new alternatives is an urgent matter in the battle against histomonosis. In the present study, intracloacal inoculation of a low-virulent H. meleagridis strain isolated after serial passages in turkeys clearly demonstrated a reduction of virulence and hence its effectiveness as a vaccine against histomonosis. The low-virulent isolate has been evaluated in a comparative experimental infection study. No mortality nor predominant caecal or liver lesions could be observed in the groups inoculated with 10(3), 10(4) or 10(5) histomonads per bird. Only dilated caeca with a yellow and foamy content could be noticed. Groups inoculated with similar doses of a virulent strain displayed a dose-related pathology and mortality up to 100%. The protective capacity of the strain with reduced virulence could be demonstrated as none of the birds cloacally inoculated with 10(3), 10(4) or 10(5) histomonads died upon challenge with 10(5)H. meleagridis of the virulent strain. Hereby, 71% of the challenge control group died. Interestingly, no or only very minor pathological lesions in the caeca and liver could be detected after challenge of the birds inoculated with the passaged histomonads. In conclusion, cloacal inoculation of the low-virulent strain obtained after serial backpassages was able to induce protection of turkeys against challenge with a virulent H. meleagridis strain.