The immunobiology of acanthocephaliasis was investigated using the model of Moniliformis moniliformis in experimentally infected, female Wistar rats. Serum was collected before infection and at 1, 2, 3, 4, 6, and 8 wk postinfection (PI). Marked eosinophilia was evident at wk 1 PI and persisted for the 8 wk. Serum immunoglobulin (Ig) M was first detected at wk 2 PI, remained relatively steady during wk 2–6, and then increased dramatically between wk 6 and 8. Serum IgG levels increased steadily from wk 4 to wk 8 PI. Serum IgE, interleukin 4 (IL-4), and interferon gamma (IFN-γ) were not detected. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis revealed consistently high antigenicity for 4 proteins of approximately 46–52, 70–78, 80–99, and 125–150 kDa that correspond to M. moniliformis proteins of 46–50, 72–78, 99, and 140 kDa, respectively, seen on SDS-PAGE. Subcutaneous injection of rats with somatic products or excretory–secretory products at 1 or 5 mg protein/kg respectively, resulted in an IgG response similar to that evoked by infection with M. moniliformis. Although a dramatic humoral immune response was mounted by rats against M. moniliformis, the response did not appear to be protective, as evidenced by egg output and worm number, size, and location.