The genetic polymorphism of four blood group systems (ABO, RH, MNSs, and DUFFY) was analyzed in two well-defined population samples coming from south-central Morocco and southeastern Spain. Both a controversial ancient common substrate and the long period of coexistence between North Africa and southern Spain during the eight centuries of the Islamic invasion of the Iberian Peninsula suggest a particular genetic relationship between northwestern Africa and southern Spain. Allele distributions in each sample are in general agreement with that expected according to the geographical and historical characteristics in the Mediterranean region. However, the differences between the Moroccan sample and other north African groups illustrate considerable genetic variability in this geographical region. In comparison with other samples from different regions of the Iberian Peninsula, the markers examined fail to demonstrate any particular affinity between the southern Spanish sample of La Alpujarra and Moroccan populations. Am. J. Hum. Biol. 11:745-752, 1999. Copyright 1999 Wiley-Liss, Inc.