Fever after bone marrow transplantation may indicate the onset of bacterial or opportunistic infection, or acute graft-versus-host disease (GVHD). In an attempt to differentiate between infection and GVHD, we prospectively studied 41 bone marrow transplants in 38 patients (24 allogeneic, 17 autologous). Elevation of C-reactive protein (CRP) proved to be a good indicator of disseminated infections. In 40 episodes of documented (11) or presumed (29) sepsis, CRP rose above 5 mg/dl in 38 episodes (95%), and above 10 mg/dl in 32 episodes (80%). The CRP concentration paralleled the clinical course of the infectious episodes. Elevated CRP values were not observed in the 15 episodes of acute GVHD without concurrent infection. High peak values of serum total IgE, ranging from 4-fold to over 4000-fold baseline, were observed posttransplant in 18/22 allogeneic BMT recipients, temporally associated with activation of acute GVHD. IgE was elevated neither in episodes of sepsis without concurrent GVHD, nor in viral or focal bacterial infections. In general, septic infections were characterized by high CRP but low IgE levels. Acute GVHD without concurrent infection was characterized by high IgE but low CRP. We conclude that CRP and serum total IgE utilized together in serial fashion are helpful in distinguishing sepsis from acute GVHD.