We have developed a method for early prenatal diagnosis of molecular disorders of collagens I and III. The method takes advantage of the fact that isolated chorionic villi contain significant amounts of collagens in their extracellular matrix (stroma) and that they synthesize collagens in vitro. After metabolic labeling of chorion villus biopsies in toto with radioactive amino acids, collagens are extracted and analyzed by SDS-PAGE. Direct staining of the gel shows collagens synthesized in vivo, whereas autoradiofluorography identifies collagens synthesized during incubation in vitro. Unlike collagens synthesized by cultured amniotic fluid cells, collagens extracted from chorionic villi are not overmodified and thus allow better identification of molecular defects. Results are available within 3 to 5 d after biopsy. Using this method, we have correctly excluded Ehlers-Danlos syndrome type IV in two pregnancies, Ehlers-Danlos syndrome type VII in one pregnancy, and lethal osteogenesis imperfecta in four pregnancies. In addition, we correctly predicted a healthy fetus and an embryo affected with lethal osteogenesis imperfecta in consecutive pregnancies from a couple in which the asymptomatic mother was a somatic mosaic for a COL1A1 G-to-A transition (Gly355Asp). Direct collagen analysis of chorion villus biopsies labeled in toto is rapid and reliable and may become the method of choice for the prenatal diagnosis of selected collagen disorders.