The focal and regional patterns of uptake, and the transmural distribution of human 131I-fibrinogen have been examined in the macroscopically normal pig aorta in vivo. Uptake of 131I-fibrinogen by focal areas of the aortic arch accumulating Evans blue dye (blue areas) was significantly greater than uptake into areas of the arch showing no dye accumulation (white areas) 2 hr after the intravenous injection of labeled fibrinogen. Not more than 5% of the 131I-fibrinogen was associated with the endothelium. Regional differences in the aortic uptake of 131I-fibrinogen were also observed; uptake into white areas of upper and lower abdominal aortic segments was significantly less than into white areas from the aortic arch. 131I-Fibrinogen activity showed a distinct transmural gradient in each of the three regions of the aorta studied, namely, aortic arch and upper and lower abdominal aortic segments. As activity was greatest in the intima and inner media, the slope of the gradients has been interpreted as indicating fibrinogen entry from the endothelial surface. 131I-Fibrinogen activity was consistently greater in areas of dye accumulation than in white areas at each level across the aortic arch, although the greatest differences were observed in the intima and innermost media. Activity across the aortic wall in both the upper and lower abdominal segments was significantly less than in the arch at each of the levels studied. In the inner 300 μm the activity was less in the lower than in the upper abdominal segments. Fibrinogen influx rates were calculated for blue and white areas from the aortic arch, and for white areas in the upper and lower abdominal aortic segments. In the arch, calculated influx was 0.82±0.13 μg/cm2/hr in white areas, and 1.73 ± 0.30 μg/cm2/hr in blue areas. In both the upper and lower abdominal aortic segments, influx was approximately half that of white areas in the aortic arch. This study has shown that plasma 131I-fibrinogen crosses the normal aortic endothelium, and that the uptake shows both regional and focal differences. It is concluded that the presence of fibrinogen or fibrin in early atheromatous lesions may reflect the demonstrated permeability of normal aortic endothelium to circulating fibrinogen.