Helicobacter pylori is a gram-negative, spiral-shaped bacterial pathogen and the causative agent for gastritis, peptic ulcer disease and classified as a WHO class I carcinogen. While the prevalence of H. pylori infections in Africa is among the highest in the world, the incidence of gastric cancer is comparably low. Little is known about other symptoms related to the H. pylori infection in Africa and the association with certain phenotypes of bacterial virulence. We established a network of study sites in Nigeria (NG) and South Africa (ZA) to gain an overview on the epidemiological situation. In total 220 isolates from 114 patients were analyzed and 118 different patient isolates examined for the presence of the virulence factors cagA, vacA, dupA, their phylogenetic origin and their resistance against the commonly used antibiotics amoxicillin, clarithromycin, metronidazole and tetracycline. We report that H. pylori isolates from Nigeria and South Africa differ significantly in their phylogenetic profiles and in their expression of virulence factors. VacA mosaicism is intensive, resulting in m1-m2 vacA chimeras and frequent s1m1 and s1m2 vacA subtypes in hpAfrica2 strains. Gastric lesions were diagnosed more frequent in Nigerian versus South African patients and H. pylori isolates that are resistant against one or multiple antibiotics occur frequently in both countries.