Since its discovery in the human stomach, the bacterium Helicobacter pylori has been branded as the cause of gastric diseases. This association is linked to the oncogenic toxin CagA produced by certain H. pylori strains, which causes severe damages but needs to be injected into the host cells to exert its toxic effect. Injection is achieved by a special bacterial transport mechanism, the Cag Type IV secretion system (Cag-T4SS). However, in nature, not all H. pylori strains infecting a patient contain the CagA toxin and the Cag-T4SS. In accordance with this, we have performed pre- and co-infection experiments of human cells in vitro with several strains of H. pylori. These experiments revealed that host cells can build up a resistance to the injection of CagA and to cellular damages associated with it. In order to further understand the mechanisms involved in this behavior, we analyzed the scope of it by looking at single aspects of infection. These included an evaluation of time of pre-infection and its effect on CagA translocation and cytokine response of the host cells to the Cag T4SS. Additionally, because of the high genetic variability of H. pylori, it was necessary to study the outreach of this phenomenon during the combination of different wild-type strains. It is remarkable that this phenomenon was not only observed in the epithelial host cell model but as well in primary cells from a hematopoietic origin, suggesting a relevance of the resistance mechanism to the CagA toxin and the Cag T4SS in the way the immune response is triggered during infection.