Two retrospective studies examining data of 7,500 lactating cows from a single herd were performed with the objective of evaluating the long-term effects of clinical disease during the early postpartum period on milk production, reproduction, and culling of dairy cows through 305 days in milk (DIM). In the first study, data regarding health, milk production, reproduction, and culling of 5,085 cows were summarized. Cows were classified according to incidence of clinical problem (metritis, mastitis, lameness, digestive problem, or respiratory problem) during the first 21 DIM (ClinD21). During 305 d of lactation, cows that had ClinD21 produced, on average, 410 kg less milk, 17 kg less fat, and 12 kg less protein compared with cows that did not have ClinD21 (NoClinD21). Although the interval to first breeding was not different between groups of interest, pregnancy rate through 305 DIM was lower in cows that had ClinD21 [adjusted hazard ratio (AHR) = 0.81]. When individual breedings were analyzed, cows that had ClinD21 presented lower rates of pregnancy per breeding for breedings performed before 150 DIM, reduced numbers of calving per breeding for breedings performed before 200 DIM, and greater number of pregnancy losses for all breedings performed through 305 DIM. The rate of culling from calving through 305 DIM was higher in cows that had a single ClinD21 (AHR = 1.79) and in cows that had multiple ClinD21 (AHR = 3.06), which resulted in a greater proportion of cows leaving the herd by 305 DIM (NoClinD21 = 22.6%; single ClinD21 = 35.7%; multiple ClinD21 = 53.8%). In the second study, data regarding postpartum health and 305-d yields of milk, fat, and protein were collected from 2,415 primiparous cows that had genomic testing information. Genomic estimated breeding values (EBV) were used to predict 305-d yields of milk, fat, and protein. Genomic EBV and predicted yields of milk, fat, and protein did not differ between cows that had ClinD21 and those that did not have ClinD21. In contrast, the observed 305-d yields of milk, fat, and protein were reduced by 345, 10, and 10 kg, respectively, in cows that had ClinD21 compared with cows that did not have ClinD21. We conclude that clinical disease diagnosed and treated during the first 21 DIM has long-term effects on lactation performance, reproduction, and culling of dairy cows, which contribute to detrimental consequences of health problems on sustainability of dairy herds. Replication of our studies in multiple herds will be important to confirm our findings in a larger population.