The objective of this negatively controlled randomized clinical trial was to compare clinical outcomes of 5-d intramammary treatment using ceftiofur hydrochloride and no antimicrobial treatment of nonsevere culture-negative cases of clinical mastitis (CM). A total of 121 cases of nonsevere (abnormal milk or abnormal milk and udder) culture-negative CM were randomly assigned to either treatment (n = 62) or negative control (n = 59) groups. Quarters assigned to treatment received 1 daily intramammary infusion with an approved commercially available product containing ceftiofur hydrochloride for 5 d. Quarters assigned to the negative control group did not receive any interventions. Enrolled cows were followed for 90 d or until the end of lactation. At enrollment, milk samples from the affected quarter were used for on-farm culture, somatic cell count (SCC) analysis, and further microbiological analysis. During the follow-up period, milk samples were collected for microbiological analysis and SCC analysis. No significant differences between treatment and negative control groups were identified for treatment failure (5% for treatment vs. 10% for negative control, n = 121), quarter-level CM recurrence (8 vs. 5%, n = 91), intramammary infection at 14 or 28 d after enrollment (13 vs. 26%, n = 86), days until clinical cure (4.2 vs. 4.0 d), days to culling (48.3 vs. 36.8 d), daily milk production (43.3 vs. 43.6 kg/cow per day), or weekly quarter SCC (5.5 vs. 5.4 log10 SCC). Days of milk discard were greater for cows assigned to the treatment group (8.5 d) compared with cows assigned to the negative control group (5.6 d). During the follow-up period, cases in the treatment group had a 50% risk reduction in IMI compared with cases in the negative control group. Irrespective of group, negative outcomes such as quarter-level CM recurrence (12%), treatment failure (12%), and culling (5%) occurred infrequently in nonsevere culture-negative cases of CM. Use of intramammary ceftiofur for treatment of nonsevere culture-negative cases of CM did not improve any economically relevant clinical outcome such as culling, milk production, or SCC.