Periparturient dairy cows exhibit impaired immune function including a decrease in neutrophil function, which is associated with an increased susceptibility to bacterial infections including mastitis in the early postpartum period. Treatment with granulocyte colony stimulating factor (G-CSF) has been shown to increase neutrophil count and enhances neutrophil function in the periparturient dairy cow. Administration of a PEGylated recombinant bovine G-CSF product (pegbovigrastim; IMR) around the time of calving has been shown to reduce the incidence of new clinical mastitis cases. The objective of this study was to investigate the efficacy and safety of IMR under herd management systems typical of those in the US dairy industry. Four trial sites located in CA, WI, WA, and CO were enrolled in this study and IMR or sterile saline (CON) was administered to primiparous (IMR n = 90; CON n = 97) and multiparous cows (IMR n = 230; CON n = 224) 7 d before anticipated calving and again within 24 h of calving. IMR cows exhibited 4–5 fold increases in circulating neutrophil numbers within 24 h of treatment initiation which persisted at least a week beyond the second dose relative to CON cows (P < 0.0001). Postpartum IMR treated animals exhibited a 35% decrease in the incidence of clinical mastitis associated with both gram-positive and negative bacteria relative to CON during the first 30 DIM (P = 0.009). Animals treated with IMR also exhibited a 52% reduction in the incidence of failure to return to estrus by 80 DIM (P = 0.03). There were no observed differences in milk yield (P = 0.45), milk composition (P > 0.57), or somatic cell (P = 0.75) count between IMR and CON cows. Similarly there were no differences in the duration of pregnancy (P = 0.39) or proportion of viable births (P = 0.55) between treatments. Overall, results of this study indicate that administration of IMR reduces the incidence of clinical mastitis during early lactation on US commercial dairy farms, and provides a novel management approach to assisting the cow during the period of periparturient immune dysfunction.