The objective of this study was to compare cultureand algorithm-guided selective dry-cow therapy (SDCT) programs with blanket dry-cow therapy (BDCT) in a multi-site, randomized, natural exposure clinical trial for the following cow-level outcomes: clinical mastitis, removal from the herd, and Dairy Herd Improvement Association (DHIA) test-day milk yield and SCC measures during the first 120 d in milk (DIM). Two days before planned dry-off, cows in each of 7 herds were randomly allocated to BDCT, culture-guided SDCT (cult-SDCT), or algorithm-guided SDCT (alg-SDCT). At dry-off, BDCT cows received an intramammary antibiotic (500 mg of ceftiofur hydrochloride) in all 4 quarters. Antibiotic treatments were selectively allocated to quarters of cult-SDCT cows by only treating quarters from which aseptically collected milk samples tested positive on a rapid culture system after 30 to 40 h of incubation. For alg-SDCT cows, antibiotic treatments were selectively allocated at the cow level, with all quarters receiving antibiotic treatment if the cow met at least one of the following criteria: (1) any DHIA test with a somatic cell count >200,000 cells/ mL during the current lactation, and (2) ≥2 clinical mastitis cases during the current lactation. All quarters of all cows were treated with an internal teat sealant. Clinical mastitis and removal from the herd events (i.e., culling or death) and DHIA test-day data from dry-off to 120 DIM were extracted from herd records. Hazard ratios (HR) for the effect of treatment group on clinical mastitis and removal from the herd during 1 to 120 DIM were determined using Cox proportional hazards regression. The effects of treatment group on test-day log e -transformed SCC and milk yield were determined using linear mixed models. Final models indicated that either SDCT program was unlikely to increase clinical mastitis risk (HR cult-SDCT/BDCT = 0.82, 95% CI: 0.58, 1.15; HR alg-SDCT/BDCT = 0.83, 95% CI: 0.63, 1.09) or test-day log e SCC (cult-SDCT minus BDCT = 0.05, 95% CI: −0.09, 0.18; alg-SDCT minus BDCT = 0.07, 95% CI: −0.07, 0.21). Risk of removal from the herd and test-day milk yield were similar between treatment groups. Findings from this study indicate that cultureor algorithm-guided SDCT can be used at dry-off without negatively affecting cow health and performance in early lactation.