The worldwide spread of antibiotic-resistant pneumococcal clones is cause for concern. In South Africa, penicillin-resistant pneumococci are mostly associated with serogroups 6 and 19, therefore, we have analyzed the clonal relationships between resistant isolates of these two serogroups. DNA fingerprinting of penicillin-binding protein genes and arbitrarily-primed PCR, have identified two penicillin-resistant pneumococcal clones of serotype 19A and serotype 6B, and a third multi-resistant serotype 19A clone, of which all three clones are predominant within South Africa's penicillin-resistant pneumococcal population. These clones are represented by strains isolated from hospitals that are widely separated in South Africa. Further studies are required to establish whether these clones have expanded in the rest of Africa or spread to other continents.