We hypothesized that at the onset of lactation, inflammation may contribute to an adaptive temporary insulin resistance to protect against hypoglycemia, but infrequent milking may reduce nutrient demands to the extent that this adaptation is unnecessary. Thirty-three multiparous Holstein cows were used to evaluate whether sodium salicylate (SS) and milking frequency (MF) alter energy status and milk yield. Cows were randomly assigned to frequent (3 × /d) or infrequent milking (1 × /d), and SS (2.3 g/L in drinking water) or control treatments in a 2 × 2 factorial design for 5 d, beginning ~24 h postpartum. Cows were fed a standard TMR to meet nutrient requirements. For measures of digestibility, TMR, refusals, and fecal samples were collected from 3 to 5 DIM. All variables, except digestibility, were analyzed as repeated measures. SS did not interact with MF for any of the variables measured (P > 0.10). MF did not alter water or DM intakes, total-tract NDF or DM digestibilities during treatment (P > 0.10). One × /d-cows produced less milk (25.0 vs. 33.1 ± 1.3 kg/d, P < 0.01) and energy corrected milk (ECM, 35.0 vs. 40.4 ± 1.6 kg/d, P = 0.02). Fat content was greater in 1 × /d-cows (5.3 vs. 4.2 ± 0.3%, P = 0.01) but protein and lactose content did not differ (P > 0.10). Three × /d-cows were in a more negative energy balance (−13.0 vs. −8.6 ± 1.2 Mcal/d of NE_L, P < 0.01), produced more ECM per unit of DM intake (2.9 vs. 2.4 ± 0.1, P < 0.01), and had lesser milk urea N concentrations (7.8 vs. 10.1 ± 0.7 mg/dL, P = 0.04). When 1 × /d-cows were switched to 3 × /d at d 6, their milk yield rapidly returned to that of 3 × /d-cows and yields were similar from wk 2 to 17 of lactation (55.8 vs. 56.8 ± 1.3 kg/d for 1 × and 3 × /d, respectively, P = 0.59). SS-treated cows produced more milk on wk 9 (62.0 vs. 55.1 ± 2.1 kg/d, P = 0.03) but the average 17-weeks milk yield did not differ (55.8 vs. 56.8 kg/d for control and SS, respectively, P = 0.59). No other impacts of SS on these outcomes were observed. Although milking frequency had expected impacts on energetics, we found no evidence that SS influences this response.