OspC and Osp17 are immunodominant proteins of Borrelia burgdorferi eliciting a clear humoral immune response in adult patients with systemic Lyme disease. In this study, the cellular immune response to B. burgdorferi and the major outer surface proteins OspC and Osp17 was investigated in children during the course of early disseminated B. burgdorferi infection. Lymphoproliferative responses to recombinant proteins were compared to the protein-specific humoral immune reaction. OspC induced a clear antibody response but elicited an even stronger cellular immune response. In contrast, a cellular as well as humoral immune reaction to Osp17 was only rarely detected. Follow-up examinations demonstrated that the lymphoproliferative response to B. burgdorferi and OspC persisted for several months after antibiotic therapy. Here, we show that in early disseminated Lyme disease of childhood, OspC is a potent antigen influencing both the humoral and cellular immunity, while Osp17 plays only a minor role in immune activation.