There is strong evidence that high yielding dairy cows are extremely susceptible to infectious diseases, and that this has severe economic consequences for the dairy industry and welfare implications. Here we present preliminary functional evidence showing that the innate immune response differs between cow breeds. The ability of macrophages (MØ) to kill pathogens depends in part on oxygen-dependent and independent mechanisms. The oxygen-dependent mechanisms rely on the generation of reactive oxygen and nitrogen species (ROS/RNS, respectively). ROS production has been shown to activate the inflammasome complex in MØ leading to increased production of the pro-inflammatory cytokine Interleukin-1β (IL-1β). Conversely RNS inhibits inflammasome mediated IL-1β activation, indicating a division between inflammasome activation and RNS production. In the present study MØ from Brown Swiss (BS) cattle produce significantly more RNS and less IL-1β when compared to cells from Holstein Friesian (HF) cattle in response to bacterial or fungal stimuli. Furthermore, BS MØ killed ingested Salmonella typhimurium more efficiently, supporting anecdotal evidence of increased disease resistance of the breed. Inhibition of autophagy by 3-methyladenine (3-MA) stimulated IL-1β secretion in cells from both breeds, but was more pronounced in HF MØ. Blocking RNS production by L-arginase completely abolished RNS production but increased IL-1β secretion in BS MØ. Collectively these preliminary data suggest that the dichotomy of inflammasome activation and RNS production exists in cattle and differs between these two breeds. As pattern recognition receptors and signaling pathways are involved in the assessed functional differences presented herein, our data potentially aid the identification of in vitro predictors of appropriate innate immune response. Finally, these predictors may assist in the discovery of candidate genes conferring increased disease resistance for future use in combination with known production traits.