Macrophages play an essential role in innate immune response to infectious pathogens. During inflammatory conditions, heme oxygenase 1 (HO-1) becomes rate limiting mechanism in the catabolism of hemoglobin originating from senescent erythrocytes to yield carbon monoxide, iron and biliverdin. Apart from the major substrate heme, the transcriptional up-regulation of hmox follows cellular exposure to agents such as bacterial endotoxins, linking its expression to a general marker of oxidative stress, thereby exerting its key regulatory function in maintaining cyto-protection and inflammatory control. However, the role of HO-1 in host pathogen interaction involving macrophages and its impact on iron homeostasis and innate immune function are incompletly understood.In murine macrophage cells (RAW264.7) and using lentivirus based transduction of hmox shRNA for gene knockdown, we observed alterations in the gene signature of iron metabolism genes, most prominent with an up-regulation of the iron exporter ferroportin. To study the relevance of these observations for host response we infected macrophages with Salmonella enterica serovar Thyphimurium known to cause acute, fatal bacteremia. The knockdown of hmox reduced the survival of Salmonella in macrophages whereas it had no effect on pathogen uptake. The improved pathogen control can be traced back to reduced iron availability for intra-macrophage bacteria and improved innate immune function as a consequence of increased ferroportin expression. Moreover, hmox knockdown further contributes to attenuation of Salmonella infection via production of reactive oxygen species (ROS). Thus, both iron restriction and ROS production resulted in NF-B activation and increase of pro-inflammatory immune response. Taken together, these data highlight a central role for HO-1 in the control of intracellular bacteria via orchestration of iron homeostasis and immune modulatory functions.