The objective was to evaluate the efficacy of intrauterine administration of chitosan microparticles (CM) for the treatment of metritis in dairy cows. Secondary objectives were to evaluate the effect of CM treatment on milk yield, reproductive performance, and survival. Holstein cows (n = 826) with metritis from 3 dairies located in northern FL were blocked by parity (primiparous or multiparous) and, within each block, randomly assigned to one of 3 treatments: CM (n = 276): intrauterine infusion of 24 g of CM dissolved in 40 mL of sterile distilled water at the time of diagnosis (D0), D2 and D4; Ceftiofur (CEF; n = 275): subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid (Excede, Zoetis) in the base of the ear at D0 and D3; Control (CON; n = 275): no intrauterine or subcutaneous treatment. A group of healthy (HTH) cows was used for comparison. Data were analyzed by generalized linear mixed models. Cure rate 12 d after treatment was greater for CEF than for CM and CON (79.6 vs. 61.2 vs. 64.7%). The cure rate was similar between CM and CON. Culling in the first 60 d postpartum (DPP) was greater for CM than CEF and CON (19.2 vs. 8.4 vs. 10.2%), which were all greater than HTH (4.3%). Culling in the first 60 DPP was similar between CEF and CON. After adjusting for concentrations at enrollment, treatment did not affect plasma concentrations of NEFA, BHB or haptoglobin. Milk yield in the first 60 DPP differed among treatments, and it was 37.3, 38.3, 39.8 and 42.4 kg/d for CM, CON, EXD, and HTH, respectively. Also, milk yield in the first 10 mo differed among treatments, and it was 35.5 ± 0.5, 35.8 ± 0.4, 36.5 ± 0.4, and 37.6 ± 0.3 kg/day for CM, CON, EXD, and HTH, respectively. The hazard of pregnancy up to 300 DIM was greater for EXD than CM and CON, which were all lesser than HTH. Median time to pregnancy was 149, 137, 131, and 113 DIM for CM, CON, EXD, and HTH, respectively. In summary, CM did not affect cure rate or hazard of pregnancy and was detrimental to milk yield and culling compared with CON. EXD increased cure rate, milk yield and hazard of pregnancy compared with CON.