Spray-dried plasma (SDP) proteins are recognized as safe, high-quality feed ingredients for livestock due to their immune modulatory components, including immunoglobulins, bioactive peptides and growth factors. The objective of this study was to investigate the effects of feeding a SDP product during the first 200 d of lactation on production and reproduction parameters in dairy cows. Nine hundred 98 Holstein cows 260 d pregnant were enrolled in a randomized design. Before calving, cows were fed a late gestation ration containing blood meal (BM; 0.8% of DM; Control, n = 503) or SDP (250 g/d; n = 495) replacing BM on N basis. After calving, Control cows were fed a lactation ration containing 0.7% BM (DM basis). Cows on SDP prepartum were fed a lactation ration that contained 400 g/d of SDP, which replaced BM. First service consisted of a timed AI protocol applied to all cows that were >44–50 DIM. Following AI, cows were examined daily for return to estrus or for confirmation of pregnancy by rectal palpation at 35–41 and 70–76 d after AI. At 72–78 DIM, cows not pregnant were enrolled into an intrauterine progesterone program. Milk production and composition were monitored on a monthly basis at one milking. All data were analyzed using a mixed-effects model with repeated measures. Reproductive data were analyzed using mixed-effects logistic regression with treatment as a fixed effect and pen as a random effect. Cows fed SDP had greater milk yield (P = 0.01; 35.7 vs 36.8 ± 0.94 kg) and milk fat (P < 0.05; 3.45 vs 3.54 ± 0.08%), but there were no differences in milk protein or in milk SCC between Control and SDP cows. Milk yield improvement in SDP cows was evident during the second month of lactation and onwards. No differences in pregnancy rate, overall conception rate, days at which pregnancy occurred or body condition score were observed between treatments. In conclusion, substitution of BM by SDP in dairy cows increased milk yield and milk fat content without affecting reproductive parameters.