The phenomenon of immunoglobulin uptake from the midgut into the hemolymph has been observed in both argasid and ixodid ticks, but the mechanism of the uptake is not known. Using capillary feeding of adult Amblyomma americanum (L.) female ticks, we investigated the role of immunoglobulin G Fc and Fab fragments in the uptake process. Intact IgG and fragments labeled with ¹²⁵I were introduced alone or as a mixture with a 10-fold molar excess of unlabeled compounds into ticks, and then the concentration of the compounds after 3 and 6 h of continuous feeding was assessed in the hemolymph. Our results showed that the uptake of Fc fragments was ≈4 times higher than Fab fragments at 6 h of the feeding and that Fc but not Fab fragments competed with uptake of intact IgG. Glycosylation of the immunoglobulins did not seem to be required for uptake. There was not a statistically significant difference between the uptake of untreated IgG and IgG treated either with periodate or N-glycanase, and untreated Fc fragments or deglycosylated Fc fragments had equal activity in competition experiments with IgG. The uptake into hemolymph of IgG and Fc fragments, but not Fab fragments, was dependent on the pH of the feeding solution and showed a maximum at ≈pH 7.0. In addition, tick midgut cells bound Fc fragments with high affinity, estimated at 21 nM; the interaction with Fab fragments seemed nonspecific. Our results suggest that Fc fragments are the major determinant for the specific uptake of immunoglobulin G into tick hemolymph.