Blood samples from patients with suspected pulmonary embolism (PE) were obtained at the time of diagnostic lung scanning to determine whether identification of those with activation of endogenous fibrinolytic pathways could serve as a screening test for PE. Cross-linked fibrin degradation products (XDPs) were measured by a quantitative enzyme-linked immunoassay with a specific monoclonal antibody (MabCO Dimertest EIA) that recognizes cross-linked D-dimer fragments and related high molecular weight fibrin derivatives containing D-dimer but that does not cross-react with fibrinogen or its plasmin degradation products. PE was present in 19 with positive pulmonary angiograms and absent in 50 with completely normal lung scans. Elevated levels of XDPs (greater than 144 ng/ml) were present in 17 of 19 patients (89%) with PE and in 28 of 50 (56%) without PE (p = 0.30). Among those with PE present, the XDP levels were (means +/- sd) 864 +/- 1,068 ng/ml (median = 470 ng/ml) compared with 285 +/- 395 ng/ml (median = 155 ng/ml) among those with PE absent (p = 0.003). For PE detection, elevated XDP levels provided a sensitivity of 89%, a specificity of 44%, a positive predictive value of 38%, a negative predictive value of 92%, and an accuracy of 57%. Among those with elevated XDP levels and PE absent, 75% had no apparent reason for XDP elevations. These data indicate that XDPs are significantly elevated in patients with PE but that, in contrast to earlier reports, measurement of XDPs among individuals with suspected PE may not be sufficiently accurate to be clinically useful in screening.