The Hpa I restriction endonuclease site polymorphism that results in some human beta globin genes being contained in a 13-kilobase (kb) DNA restriction fragment rather than in the usual 7.6-kb fragment has been reported to be in linkage disequilibrium with the beta S mutation. The frequency of the 13-kb fragment among Baltimore black sickle cell (SS) disease patients (58%) is lower than that reported for San Francisco black SS disease patients (87%) and similar to that reported for such New York patients (59%). There is, then, considerable heterogeneity among American black populations. Therefore, for the purposes of prenatal diagnosis, the frequency in the particular population at risk should be established. When the frequency of association of the 13-kb fragment and the beta S mutation is low, the linkage phase must also be established. When the linkage phase is known, the Hpa I pattern alone can exclude SS disease 54% of the time for Baltimore AS X AS couples.