Plasmodium yoelii and Schistosoma mansoni co-infections were studied in female BALB/c mice aged 4-6 weeks to determine the effect of time and stage of concomitant infections on malaria disease outcome. Patent S. mansoni infection in BALB/c mice increased malaria peak parasitemia and caused death from an otherwise non-lethal, self-resolving P. yoelii malaria infection. Exacerbation of malaria parasitemia occurred during both pre-patent and patent S. mansoni infection resulting in a delay of 4-8 days in malaria parasite resolution in co-infected mice. Praziquantel administered to mice with patent schistosome infection protected from fatal outcome during co-infection. However, this treatment did not completely clear the worm infestation, nor did it reduce the peak malaria parasitemia reached, which was nonetheless resolved completely. Hepatosplenomegaly was more marked in schistosome and malaria co-infected mice compared to either infection separately. The results suggest a complex relationship between schistosome co-infection and malaria disease outcome in which the timing of malaria infection in relation to schistosome acquisition is critical to disease outcome and pathology.