The resistance of cotton rats, Sigmodon hispidus to Nippostrongylus brasiliensis infection was examined and compared the response to that of the susceptible Indian soft-furred rat, Millardia meltada. After a primary infection with infective third-stage N. brasiliensis larvae (L3), the number of eggs in feces and adult worm recovery rates from the small intestine of cotton rats were significantly lower than in the controls. To determine whether cotton rat resistance was observed during the migratory phase or the intestinal phase, cotton rats and control animals were challenged subcutaneously with L3 or intraduodenally with adult worms, and larval recovery from lungs and adult worm burden were evaluated. The recovery rate of larvae from the lungs of cotton rats was about five-fold lower than from controls. Adult worm recovery from the small intestine of cotton rats was also lower than that from the controls, but the difference (two-fold lower) was smaller than that observed for lung recovery. Carbon treatment at a dose of 250-500 mg/kg effectively increased larval worm recovery from the lungs of cotton rats. However, this treatment had no effect on worm recovery from the intestine after intraduodenal implantation of adult N. brasiliensis. These results suggest that macrophage function have important role in the expression of strong resistance during the migratory phase of N. brasiliensis infection in cotton rats.