To assess the ability of Dermacentor variabilis larvae to feed on mice during repeated infestations, known numbers of larvae were confined to the skin of BALB/c mice within plastic capsules, and different skin sites were used in four successive infestations. In secondary infestations larval feeding appeared to be enhanced, but in subsequent infestations the mice expressed acquired tick resistance, manifested by reduction in numbers of engorged larvae and in weights of fed larvae. Resistance, once established, was still demonstrable four weeks after the previous infestation. Histological examination of skin biopsies from BALB/c mice undergoing repeated infestations revealed slight reactions to primary infestations and increasingly severe responses in subsequent infestations. The latter reactions included prominent participation of mast cells and eosinophils, many of which were degranulated close to tick bite sites. It is suggested that these cells might play a role in the expression of murine tick resistance.