Splenectomy results in an increased risk of sepsis. The autogenous transplant of the spleen is an option for preserving splenic functions after total splenectomy. In this study, the capacity of animals undergoing autogenous spleen transplantation to respond to Staphylococcus aureus infection was investigated. BALB/c mice were divided into three groups: splenectomy followed by autotransplantation in the retroperitonium (AT), splenectomized only (SP) and operated non-splenectomized sham control (CT). Thirty days after surgery the mice were infected intravenously with S. aureus. Splenectomized mice had a higher number of colony-forming units (CFU) of S. aureus in liver and lungs in comparison with either AT or with CT mice (P < 0.05). Higher CFU numbers in lung of SP mice correlated with elevated production of interleukin-10 associated with a lower production of interferon-gamma and tumour necrosis factor-alpha. However, systemically, the level of tumour necrosis factor-alpha was higher in the SP group than in CT or AT. Lower titres of specific anti-S. aureus immunoglobulin (Ig)M and IgG1 were observed 6 days after infection in SP mice in comparison either with the AT or CT groups. Thus, splenectomy is detrimental to the immune response of BALB/c mice against infection by S. aureus which can be re-established by autogenous implantation of the spleen.