Previous investigators suggested that increased plasma levels of the terminal complement complex (sC5b-9) are an early marker for the development of adult respiratory distress syndrome (ARDS) in septic patients. We asked whether an increase in sC5b-9 was also associated with the development of ARDS from other etiologies and whether sC5b-9 measurements consistently reflected complement activation in vivo. We evaluated 75 patients with sepsis, trauma, hypertransfusion, multiple fractures, aspiration, or pancreatitis who were at risk for ARDS but did not develop the syndrome and 23 patients with similar histories who did develop ARDS. Of the latter patients, seven were identified and studied both when they were at risk and when they had ARDS. Serial blood samples were obtained and analyzed for the complement activation products Bb, Ba, C4d, C3d, IC3b, and sC5b-9. All but one of the patients studied had levels of one or more complement fragments that were greater than 2 SD above the mean obtained from 18 normal subjects. In contrast to the report referred to previously, none of the fragments measured, including sC5b-9, was a specific indicator of ARDS, and no combination of complement fragments predicted which patients at risk would develop ARDS. Patients demonstrated evidence of activation of the classical pathway only, alternative pathway only, or both pathways, but none of these was associated with greater risk or severity of disease. In addition, in several patients only late components were activated, suggesting that enzymes other than those derived from complement activation may be responsible. In conclusion, complement can be activated by a variety of mechanisms in critically ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)