Background. Loa loa has emerged as an important public health problem due to the occurrence of immunemediated severe posttreatment reactions following ivermectin distribution. Also thought to be immune-mediated are the dramatic differences seen in clinical presentation between infected temporary residents (TR) and individuals native to endemic regions (END). Methods. All patients diagnosed with loiasis at the National Institutes of Health between 1976 and 2012 were included. Patients enrolled in the study underwent a baseline clinical and laboratory evaluation and had serum collected and stored. Stored pretreatment serum was used to measure filaria-specific antibody responses, eosinophilrelated cytokines, and eosinophil granule proteins. Results. Loa loa infection in TR was characterized by the presence of Calabar swelling (in 82% of subjects),markedly elevated eosinophil counts, and increased filaria-specific immunoglobulin G (IgG) levels; these findings were thought to reflect an unmodulated immune response. In contrast, END showed strong evidence for immune tolerance to the parasite, with high levels of circulatingmicrofilariae, few clinical symptoms, and diminished filaria-specific IgG. The striking elevation in eosinophil counts among the TR group was accompanied by increased eosinophil granule protein levels (associated with eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines. Conclusions. These data support the hypothesis that differing eosinophil-associated responses to the parasite may be responsible for the marked differences in clinical presentations between TR and END populations with loiasis.