Parasitological and immunological responses of genetically resistant and random-bred lambs to primary and secondary infection with H. contortus were studied. Resistant lambs had higher faecal egg counts and total worm burdens than the random-bred lambs following the primary infection. As there were no significant differences in serum and antibody levels, mucosal mast cells, circulating and tissue eosinophils between the two groups, it is inferred that what ever the underlying mechanism it was an innate characteristic. In contrast to primary infection, resistant lambs had significantly lower faecal egg counts and worm burdens than the random-bred lambs on secondary infection. Resistant lambs also exhibited significantly higher antibody levels, mucosal mast cell hyperplasia and mucosal eosinophilia in response to a challenge infection than the random-bred lambs. Furthermore, levels of mast cell hyperplasia and anti-Haemonchus antibodies correlated positively with the resistance status of the host. Taken together these results suggest that the genetic resistance of sheep to H. contortus results from the expression of an acquired immune response, and that anti-parasite antibodies and mast cell-derived mediators may play an important role in genetically determined resistance of sheep to haemonchosis.