A patient with classical cold agglutinin disease initially experienced haemolytic episodes during cold exposure. However, with advancing disease cold-induced haemolysis ceased and was substituted with a haemolytic disposition at elevated body temperatures. To investigate this paradoxical development of disease manifestations, we performed a clinical and immunological study. Our results indicate that the patient's complement system became exhausted during the later phase of his disease, probably due to continual consumption of complement components. Initially, the patient had slightly decreased C4 concentrations and moderately reduced total haemolytic activity (CH50). Later C4 fell to undetectable levels and CH50 declined to zero. The increased haemolytic activity experienced during febrile episodes is probably due to a cold agglutinin with a high thermal amplitude, combined with enhanced synthesis of complement molecules during the acute phase response. Although C4 concentrations never increased to detectable levels during infections or inflammations an acute phase reaction was determined each time, as evidenced by increased concentrations of CRP. By reconstituting the patient's serum with active complement from donor serum or plasma, increased haemolytic activity was observed. These results indicate that some patients with cold agglutinin disease may experience deleterious haemolytic consequences if transfused with plasma-containing blood products.