Attempts were made to evaluate the protective efficacy of Brugia malayi thioredoxin peroxidase (BmTPX) in a mouse model. Mice immunized with a protein vaccine containing rBmTPX developed higher titres (1:5,000/1:10,000) of anti-BmTPX antibodies, compared with the mice immunized with the alum control. There was a higher level of cellular proliferative response in mice immunized with BmTPX compared with the alum control (p < 0.05), which was associated with a Th2-type of response. In order to compare the prophylactic efficacy of BmTPX in natural infection, we evaluated the human immune responses to these antigens in endemic normals (EN) and infected individuals (microfilaraemic and chronic pathology). Results showed that EN subjects carry BmTPX-specific IgG1 and IgG3 circulating antibodies against natural exposure to filariasis. Peripheral blood mononuclear cells from EN subjects responded strongly to rBmTPX by proliferating, as well as by secreting interferon (IFN)-gamma (Th1) and IL-5 (Th2), a mixed type of response to rBmTPX. In the case of infected individuals, there was no IFN-gamma or IL-5 response. Thus, there was a clear dichotomy in the cytokine production by infected versus EN individuals. Our findings suggest that BmTPX may be a suitable antigen candidate for lymphatic filariasis, but a further study is still required.