The periparturient period of dairy cows is characterized by changes in innate inflammatory status (IS) but the physiological origin of these changes remains unclear. The objectives of this study were to investigate the effects of breed and feed efficiency on IS during the periparturient period mid-lactation and a sequential nutritional challenge (SNC) of 4 successive 4-d feed restriction (FR) periods. Fourteen Holstein (HOLS) and 14 Montbeliarde (MONT) multiparous cows were selected a posteriori from 40 animals based on extreme residual feed intake (RFI) during the first 10 wk of lactation and classified as RFI+ (0.42 to 2.34 kg DMI/d n = 14) or RFI- (-2.38 to -0.44 kg DMI/d n = 14). Cows were studied from wk -3 to +22 of lactation. Starting at 86 ± 9 DIM cows underwent 4 periods of 4-d FR to meet 50% of individual net energy requirements (FR1 FR2 FR3 FR4) followed by 10 3 3 and 10 d recovery periods of ad libitum intake respectively. Blood samples were collected from the coccygeal vessels before morning feeding on wk -3 +2 +12 and +22 of lactation and on d 0 and 4 of each FR. Plasma was analyzed using the Milliplex Bovine Cytokine/Chemokine Panel (Merck Germany). For both breeds tumor necrosis factor Alpha (TNFalpha) IL-1alpha IL-10 monocyte chemoattractant protein-1 (MCP-1) and IL-6 were significantly lower on Wk+2 than Wk-3 and remained steady through lactation but IL-8 increased at Wk+2 compared with Wk-3. Concentrations in TNFalpha IL-10 MCP-1 and IL-8 were higher in HOLS than MONT. Concentration in macrophage inflammatory protein -1beta (MIP-1beta) was higher in RFI+ than RFI-. The significant FR effects on innate IS were small and not systematic across FR1 to FR4. The SNC induced relatively small changes in cytokine and chemokine concentrations indicating that negative energy balance did not affect IS despite consistent metabolic responses. Breed phenotypic feed efficiency and repeated feed restrictions had limited effects on IS.