Paired Ig-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms are expressed by many hematopoietic cells, including B lymphocytes and myeloid cells. To determine the functional roles of PIR-A and PIR-B in primary bacterial infection, PIR-B-deficient (PIR-B−/−) and wild-type (WT) control mice were injected iv with an attenuated strain of Salmonella enterica Typhimurium (WB335). PIR-B−/− mice were found to be more susceptible to Salmonella infection than WT mice, as evidenced by high mortality rate, high bacterial loads in the liver and spleen, and a failure to clear bacteria from the circulation. Although blood levels of major cytokines and Salmonella-specific Abs were mostly comparable in the two groups of mice, distinct patterns of inflammatory lesions were found in their livers at 7–14 days postinfection: diffuse spreading along the sinusoids in PIR-B−/− mice vs nodular restricted localization in WT mice. PIR-B−/− mice have more inflammatory cells in the liver but fewer B cells and CD8+ T cells in the spleen than WT mice at 14 days postinfection. PIR-B−/− bone marrow-derived macrophages (BMMφ) failed to control intracellular replication of Salmonella in vitro, in part due to inefficient phagosomal oxidant production, when compared with WT BMMφ. PIR-B−/− BMMφ also produced more nitrite and TNF-α upon exposure to Salmonella than WT BMMφ did. These findings suggest that the disruption of PIR-A and PIR-B balance affects their regulatory roles in host defense to bacterial infection.