Naturally acquired immunity to the parasite Plasmodium plays an important role in protection against malaria infections, which remain a widespread cause of morbidity and mortality worldwide. No evidence exists of sterile immunity to the disease and the development of sustained clinically protective antibody responses has been shown to require repeated infections. While many studies have focused on the complex nature of these responses against the antigenically diverse parasite, few have addressed the effect of malaria infection on the generation of memory B cell (MBC) responses. A study of children in areas of high seasonal transmission revealed a delay in malaria-specific MBC generation despite continual exposure to the parasite. In contrast, in a low transmission setting, lasting MBC responses were detected in adults following a single exposure to the parasite. These data indicate clinical malaria infe ctions may hinder the generation and maintenance of malaria-specific MBC populations. To further investigate this notion, C57BL/6 mice were infected with P. berghei ANKA or immunised with an equivalent antigenic load of attenuated parasites, and mice were drug-cured prior to the onset of severe malaria symptoms. Long-lived populations of B cells are generated during the germinal centre (GC) reaction in secondary lymphoid organs, such as the spleen, and histological studies of this organ revealed that clinical malaria infections profoundly impede the correct generation of GC structures. Further, compared to immunised control animals, infected animals had reduced numbers of GC B cells and T follicular helper cells, both critical to an effective GC reaction. Importantly, the frequency, isotype switching and relative affinity maturation of long-lived plasma cell populations appeared to be compromised by malaria infections relative to immunised controls. Taken together these data indicate that clinical malaria negatively impacts the development of long-term humoral immunity by disrupting critical early stages in the development of the B cell response.