During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-gamma-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-alpha protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-gamma production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-gamma production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.