The objective of this study was to evaluate the impact of clinical diseases in the early postpartum on culling, production and reproduction of dairy cows up to 305 d in milk (DIM). Detailed data regarding health, production, reproduction, and culling of 5,085 cows that calved in 2012 in a single herd were summarized. Of all cows, 1,534 cows had at least one clinical problem (i.e., metritis, mastitis, lameness, digestive, or respiratory problem) in the first 21 DIM (ClinDis21), which represented 65.7% of all cows presenting a clinical problem up to 305 DIM. Clinical cases diagnosed within 21 DIM represented 54.3% of all clinical cases occurring up to 305 DIM. The impact of ClinDis21 on dependent variables was then accessed. Statistical analyzes of binary and continuous dependent variables were performed using the GLIMMIX procedure of SAS fitting the correct data distribution. Survival analyses were performed using the PHREG procedure of SAS. The rate of culling was increased by ClinDis21 (adjusted hazard ratio [AHR]: 1.96, confidence interval [CI]: 1.75–2.18, P < 0.01) and resulted in a greater proportion of cows leaving the herd by 305 DIM (38.2 vs. 22.6%; P < 0.01). The effect of ClinDis21 on culling rate was observed (P < 0.01) even when cows that left the herd within 21 DIM were excluded. ClinDis21 did not affect (P = 0.82) time to first breeding, but reduced pregnancy rate (AHR: 0.82, CI: 0.77–0.89, P < 0.01) and the proportion of cows becoming pregnant by 305 DIM (85.1 vs 90.6%, P < 0.01). The effect of ClinDis21 on pregnancy rate was observed (P < 0.01) even when cows that became pregnant at the first breeding were excluded. Moreover, 305-d yields of milk, fat, and protein were all reduced (P < 0.01) by ClinDis21 (milk: 10,012 vs. 10,465 kg; fat: 359 vs. 378 kg; protein: 290 vs. 303 kg) and these differences could not be explained by the yields observed in the first 21 DIM. All effects of ClinDis21 described herein were augmented by the incidence of multiple diseases, characterizing additive effects. In conclusion, clinical diseases in the first 21 DIM have long-term effects on culling, reproduction and milk production of dairy cows.