In the present study, we report the ability of in vitro cultured CD4⁺ T cells, generated following immunization with dead blood stage P. yoelii parasites, to mediate protection against homologous challenge infection in reconstituted nude mice. P. yoelii‐specific T cell line cells produced IFN‐γ after in vitro stimulation with specific antigen, and were protective when adoptively transferred into athymic nude mice. Following transfer of P. yoelii‐specific T cell lines into nude and SCID mice, elevated levels of nitric oxide (NO) were detected during the first week of infection at a time when parasitaemias were suppressed. However, in vivo blocking of NO production through administration of L‐NMMA, an inhibitor of NO synthase, increased mortality, but did not alter the course of primary parasitaemia in P. yoelii‐specific T cell line‐reconstituted nude mice. In addition, a P. yoelii‐specific CD4⁺ T cell clone, which produced IFN‐γin vitro, afforded sterile protection via mechanisms other than NO. By ELISA, antibodies were undetectable on all but one day (day 79) post T cell clone transfer and parasite challenge, where very low levels of antibodies were detected, with some evidence of recognition of malaria proteins by Western blot. Collectively, our data suggest that T cell effector functions, independent of NO production and in the absence of high levels of parasite‐specific antibodies, can contribute to sterile immunity to P. yoelii.