Meningeal worm (Parelaphostrongylus tenuis) is a neurotropic nematode of ungulates in eastern North America. Lack of an effective diagnostic test increases the concern of translocating potentially infected ungulates into western North America, where P tenuis does not occur naturally. In an attempt to identify serodiagnostic molecules, we determined (1) whether elk (Cervus elaphus) experimentally infected with P. tenuis produce antibodies against infective larvae or adult worms, and (2) if sera consistently recognize antigens that distinguish P. tenuis from a common nematode parasite of elk, the lungworm Dictyocaulus viviparus. Each of 10 elk were exposed to 15 or 300 infective P. tenuis larvae. Serum was collected (0, 41, and 83 days post-exposure and at necropsy) and monitored for antibodies using the enzyme-linked immunosorbent assay (ELISA) and immunoblot. When reactivity of sera with larval P. tenuis protein was compared (day 0 versus 83), ELISA values were significantly higher on day 83 for elk exposed to 15 or 300 parasites. Likewise, ELISA values using protein of adult P. tenuis were higher for elk exposed to 300 larvae. Immunoblots showed that sera from elk, with adult worms in the central nervous system, consistently recognized the 25–27, 28–30, and 34–36 kDa antigens of infective larvae after 83 days. However, many D. viviparus molecules were found to cross-react with antibodies formed against meningeal worm antigens. Use of adult worm proteins for serodiagnosis appears limited, because no protein was consistently recognized by sera collected from elk exposed to 15 larvae. We believe that development of a reliable diagnostic test for meningeal worm requires more research addressing cross-reactivity and detection of P. tenuis during the incubation stage.