The objective of this study was to evaluate the effect of intramuscular (i.m.) ceftiofur (2.2 mg/kg) on important outcomes of systemically mild clinical mastitis episodes in lactating dairy cattle. Cows with clinical mastitis were randomly assigned to a treatment group: pirlimycin intramammary (i.m.m.) (n = 35), pirlimycin i.m.m. and ceftiofur i.m.m. (n = 36), cephapirin i.m.m. (n = 40), cephapirin i.m. and ceftiofur i.m. (n = 33). Sixty-nine, 22, and 9% of initial cultures were gram-negative, gram-positive, and mixed, respectively. Logistic regression analysis showed no significant associations between treatment groups and loss of quarter, recurrence, or culling. Mixed infections, positive milk culture at 7 d after leaving hospital pen, decreased rumen motility, and absence of udder firmness were associated with increased odds of mastitis recurrence. The results suggest that i.m. ceftiofur treatment has no beneficial effects on the outcome of systemically mild clinical mastitis.