Induration is a characteristic feature of delayed-type hypersensitivity skin reactions and is the usual measure of their intensity. The precise basis of induration has not been established, although activation of the clotting system with consequent fibrin deposition has been clearly implicated. In this study, two subjects with congenital afibrinogenemia, a genetic defect in fibrinogen synthesis, were skin tested with standard microbial antigens: streptokinase-streptodornase, monilia, mumps, and tuberculin purified protein derivative. One positive delayed reaction from each subject was biopsied at 40-48 h and compared with 23 biopsies of similar skin tests in normal volunteers. The eight skin tests in the afibrinogenic subjects lacked induration, although the erythema was similar in size (10-34 mm in diameter), intensity, and time-course to those in normals. Biopsies from the two strongest reactions from the afibrinogenemic subjects showed a typical perivascular mononuclear infiltrate. No more than traces of fibrin/fibrinogen were detected by immunofluorescence, in striking contrast to the abundant fibrin/fibrinogen deposition in 23 positive, indurated reactions in normal subjects. These findings indicate that fibrinogen itself is essential for the development of induration in delayed-type skin reactions in man. As judged by 1-mum sections and fluorescence, this is probably a result of the formation of an extravascular fibrin gel.