In vitro IgM production by cells from patients with Lyme disease rose during the illness in those studied soon after onset, but fell from elevated levels in those initially studied later than 1 week after onset. Borrelia burgdorferi stimulated normal and patients' cells produced IgM, with cells from acutely ill patients producing the most; production fell during convalescence. Patients with active Lyme disease and those destined for later manifestations often had serum agglutinins for heterologous red blood cells. Thus, there is in vitro and in vivo B cell hyperactivity in Lyme disease caused by B. burgdorferi. Both mitogenic and antigenic stimulation of B cells may induce the humoral response seen in complicated Lyme disease.