In this randomized controlled trial on four commercial grazing dairy farms, we investigated whether pegbovigrastim (PEG) treatment affects clinical mastitis (CM) and uterine disease (i.e. retained placenta (RP), metritis and endometritis) occurrence during a full lactation. The association of prepartum body condition score and prepartum non-esterified fatty acid (NEFA) concentration with disease occurrence was also evaluated. Holstein cows were randomly assigned to one of two treatments: first PEG dose approximately 7 d before the expected calving date and a second dose within 24 h after calving (PEG) compared to untreated controls (Control). In total, 2,153 animals were included in the study: 733 primiparous cows (Control = 391, PEG = 342) and 1420 multiparous cows (Control = 723, PEG = 697). Treatment effects were evaluated with generalized linear mixed models and Cox’s proportional hazard models. Treatment with PEG reduced the occurrence of a first case of CM during the first 30 days in milk (DIM) by 24.6% and reduced the hazard of a first case and the rate of total cases of CM during the full lactation. All PEG treatment effects were independent of parity. Prepartum body condition score interacted with PEG treatment: in over-conditioned cows, PEG reduced the occurrence of a first case of CM during the first 30 DIM by 49.5%. The hazard analysis of a first case of CM during the full lactation suggested that the preventive effect of PEG disappeared with increasing DIM. Treatment with PEG did not affect the occurrence of RP or metritis. Pegbovigrastim treated cows with metritis subsequently showed a reduced occurrence of endometritis compared to control cows with metritis. Pegbovigrastim reduces the occurrence of CM particularly in cows at risk of elevated lipid mobilization, and PEG ameliorates the uterine healing process in cows that experienced metritis.