To identify fetal histologic features characteristic of specific chromosomal anomalies, we reviewed histologic slides of 415 cases, including therapeutic and spontaneous abortuses, stillbirths, and perinatal deaths. These included 126 cases (30%) with karyotypically confirmed trisomy 21 and 23 cases (5.5%) with trisomy 13. Two histologic abnormalities of the fetal heart were identified that correlated with specific karyotypic abnormalities: (1) a discrete central papillary muscle calcification was present in 14 of 85 (16%) cases with trisomy 21, in seven of 18 (39%) cases with trisomy 13, and in six of 255 (2%) controls (P less than .001); and (2) a focal ventricular epicardial lymphocytic infiltrate was present in 22 of 93 (24%) cases with trisomy 21 versus nine of 284 (3%) controls (P less than .001). When both histologic abnormalities coexisted, trisomy 21 was present in five of six cases (83%). Neither histologic finding was significantly associated with fetal or maternal infection or congenital heart defects. In a restricted prospective study of the hearts of fetuses with trisomy 21, papillary muscle calcification was demonstrated by specimen radiographs in four of six (67%) cases; one case was studied by specimen ultrasonogram, which identified a papillary muscle echodensity. We conclude that (1) a focal ventricular epicardial lymphocytic infiltrate is characteristic of trisomy 21, (2) papillary muscle microcalcifications are characteristic of trisomies 13 and 21, and (3) further studies are needed to determine whether papillary muscle calcification might be useful in antenatal ultrasonographic screening for chromosomal anomalies.