The ability of guinea pigs to acquire resistance to Dermacentor andersoni and Amblyomma americanum was determined by repeatedly infesting separate sets of guinea pigs with tick larvae. Resistance was measured in terms of reduced numbers successfully engorging and reduced weight of those ticks that engorged. An 83% reduction in numbers of larvae engorging and a 64.5% reduction in the weight of engorged larvae were seen between the first and second infestations with D. andersoni. Guinea pigs exhibited considerably less resistance to A. americanum the third time they were exposed to this species than did guinea pigs infested twice with D. andersoni. Feeding success was only 30.8% less than the initial percentage that engorged, and the percentage weight reduction was 35. During the challenge infestations, sizable fluid-filled vesicles formed on ears of the guinea pigs used as hosts for D. andersoni or A. americanum. Cross-resistance was evaluated by dividing D. andersoni-resistant animals into groups and challenging them with D. andersoni D. variabilis, A. americanum, or Ixodes scapularis. Appreciable cross-resistance was apparent between the two Dermacentor species. The weights of the A. americanum and I. scapularis were significantly reduced, but not the number that engorged. When A. americanum-resistant guinea pigs were challenged, they were cross-resistant to D. variabilis but not to D. andersoni. Skin tests on guinea pigs in which extracts of tick salivary glands were used as the antigens did not conclusively reflect the same patterns of cross-reactions noted in the tests of cross-resistance.