Guinea pigs sensitized to tick feeding by a previous infestation express immune resistance when challenged. This state is associated with large accumulations of eosinophils, and especially of basophils, at cutaneous sites of tick feeding. The present study shows that primary and secondary tick feeding stimulate blood eosinophilia and basophilia that reflect the infiltration of these cells in the skin. Primary feeding of Amblyomma americanum larvae resulted in a mean tick yield of 81%, mean tick weight of 0.91 mg and a feeding period of 3-5 days. Blood eosinophils and basophils began to rise on day 2 and reached peak 3-fold increases on day 4, the time of maximum tick drop-off. Secondary feedings 26 days later resulted in a mean tick yield of 45%(52% tick rejection), mean tick weight of 0.71 mg (22% weight decrease) and a mean feeding period of 4-6 days with maximum detachment on day 5. Prior to secondary tick feeding, both eosinophil and basophil levels were greater than in tick-free animals. Eosinophil levels peaked at day 4 to a level three times greater than in primary tick hosts. Basophil levels in secondary hosts exhibited minor elevations until day 6 when they were increased significantly, reaching a peak level of 33% higher than that observed in primary feedings. This study demonstrates that blood eosinophils and basophils respond quickly and significantly to primary tick feeding and undergo secondary responses of greater magnitude in response to subsequent tick challenge. However, challenge feeding resulted in a large blood eosinophilia with a modest blood basophilia. This may reflect the balance between bone marrow production and cutaneous accumulation of these cells at sites of tick rejection. Recruitment of eosinophils and basophils from the blood to the tissue site of tick feeding may contribute to the tick resistance mechanism.