ABSTRACT: Blanket dry cow therapy (DCT) is a major contributor to overall antibiotic usage on dairy farms in the United States. With low prevalence of intramammary infections at dry-off in US herds today, alternative DCT approaches have been the focus of much research. We hypothesized that complete cessation of DCT [i.e., use of internal teat sealants (ITS) only at dry-off] could be a practical alternative to blanket DCT in well-managed herds. The objective of this negatively controlled clinical trial was to determine the effects of DCT on clinical mastitis (CM) and removal from the herd during the dry period and the first 200 d of the subsequent lactation in multiparous dairy cows treated with only ITS at dry-off. As a secondary objective, we conducted exploratory analysis to identify subpopulations in the herd (based on parity, previous CM history, and dry-period length) where DCT would not affect postcalving udder health, to generate hypotheses about potential alternative selective DCT programs. The study was conducted in a commercial dairy herd in South Dakota from June 2020 to January 2021. Dry-off sessions (n = 43) were scheduled such that all cows at a given session were dried off using ITS alone (ITS only, n = 20 sessions, n = 1,108 cows) or an intramammary DCT product containing 500 mg of cloxacillin (Dry-Clox, Boehringer Ingelheim) followed by ITS (ITS+ABX, n = 23 sessions, n = 1,331 cows). Culling and CM events were recorded by farm workers who were blinded to the treatment status of cows. Hazard ratios (HR) for the effects of the treatment group on CM and removal from the herd were estimated using multivariable Cox proportional hazards, adjusting for the clustered treatment allocation strategy. Risk of removal from the herd during the dry period was lower in ITS+ABX than ITS-only cows (1.1 vs. 2.7%; HR = 0.45; 95% CI: 0.25 to 0.81). Risk of removal from the herd during the first 200 d of lactation was similar in ITS+ABX and ITS-only cows (17.3 vs. 18.0%; HR = 0.98; 95% CI: 0.82 to 1.18). Risk of CM during the first 200 d of lactation was lower in ITS+ABX cows (6.9%; HR = 0.56; 95% CI: 0.41 to 0.76) compared with ITS-only cows (13.4%). The beneficial effects of DCT on CM and removal from the herd were consistently observed across strata of parity, previous CM history, and dry-period length, indicating that no subpopulations could be identified to withhold DCT. The findings from this study indicate that the omission of DCT from the dry-off procedure, when udder health is not taken into consideration, in multiparous cows can have a negative effect on cow health and welfare. Findings from previous research suggest that culture- or algorithm-guided selective dry cow therapy are likely to be safer approaches to improving antibiotic stewardship.