Aeromonas salmonicida subsp salmonicida (A. salmonicida) is one of the most significant pathogens of salmonids and is the agent of furunculosis, a disease which causes severe losses in aquaculture worldwide. A. salmonicida is characterized by a type III secretion system (T3SS) responsible for the translocation into the host’s cells of several toxins and effector proteins. T3SS together with the secreted toxins and effector proteins are encoded by a large conjugative plasmid of 150 kb which can be lost or undergo insertion sequence dependent deletions when grown in stressful conditions, including growth at temperatures above 20°C. A number of publications suggested a possible role of the T3SS in impacting the immune system of the fish host, however, conclusive evidence of this has yet to be provided. In order to assess this hypothesis we infected different groups of rainbow trout (Oncorhynchus mykiss) with distinct strains of A. salmonicida, either carrying a fully functional T3SS or a functionally impaired T3SS or finally a “cured” A. salmonicida strain devoid of T3SS. A series of markers reflecting the putative Th-1, Th-2, cell-mediated and T-regulatory cell immune response in fish were selected in order to evaluate the impact, if any, of the different T3SS and ultimately of its presence or absence on the host immune response. Following experimental infection carried out by an intra-coelomic injection of either one of the selected A. salmonicida strains, the fish were sampled at 1, 2 and 5 days post-infections, respectively. Our results indicate that the infection with an A. salmonicida strain either carrying a fully functional or a secretion-impaired T3SS is associated with a strong and persistent immune suppression. However, the infection appears to be fatal only in presence of a fully functional T3SS. In contrast, the absence of T3SS is neither associated with immune suppression nor fish death.