Autoantibodies specific to the cytoplasmic components of neutrophils and monocytes are associated with vasculitis and other idiopathic inflammatory disorders. In this study, using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assays, sera from patients with acute and chronic infection were examined for the presence of anti-neutrophil and anti-monocyte antibodies: cystic fibrosis (n = 23), acute appendicitis (n = 22), tuberculosis (n = 26), acute gastroenteritis (n = 38), bronchiectasis (n = 9) and chronic granulomatous disease (n = 6). Sera from patients with Wegener's granulomatosis (n = 14), rheumatoid factor positive (n = 15) and healthy volunteers (n = 20) were used as positive and negative controls. In patients with chronic infection, using an ELISA assay, antibodies reactive with neutrophil or monocyte components (% reacting with monocyte components in parenthesis) were found in: 70% (39%) of patients with cystic fibrosis, 4% (38%) of patients with tuberculosis, 0% (33%) of patients with bronchiectasis and 0% (17%) of patients with chronic granulomatous disease. When these sera were examined using an immunofluorescence assay, all of the positive samples were found to react with the cytoplasmic component of neutrophils or monocytes. In patients with acute infection no antibodies (either IgG or IgM) were detected against neutrophils or monocytes. These findings imply that antibodies directed against neutrophil cytoplasmic components are predominantly associated with chronic pyogenic infection and antibodies specific to monocyte cytoplasmic components are predominantly associated with chronic granulomatous infection. This mirrors the findings in idiopathic inflammatory disease where anti-monocyte antibodies are associated with granulomatous disorders such as sarcoidosis, and anti-neutrophil antibodies are associated with neutrophilic disorders such as ulcerative colitis. These results suggest that chronic stimulation of phagocytes by infectious agents may result in the generation of a humoral response against phagocyte cytoplasmic components. This furthers our understanding of humoral immune responses against phagocytic cell components during infection.