Objective To evaluate the effects of different antibiotic regimens applied in orthopedic joint surgery through multi-departmental collaboration on optimizing nursing human resource allocation and reducing medical consumables expenditure， and to verify whether its safety in preventing infection is non-inferior to the traditional regimen. Methods A retrospective cohort study was conducted. A total of 1 948 patients from the Department of Knee Surgery between May 10， 2021， and May 22， 2024， were selected. A subgroup analysis of inflammatory markers was performed on 303 of these patients （44 hip joints， 259 knee joints）. Patients were divided into a single-dose group （972 cases） and a multiple-dose group （976 cases） based on the antibiotic regimen. The single-dose group received only one postoperative dose of antibiotics， while the multiple-dose group received multiple postoperative doses. The primary outcome was the relationship between the number of antibiotic packages used and the incidence of prosthetic joint infection （PJI） within 12 months postoperatively. Secondary outcomes included inflammatory markers： white blood cell count （WBC）， neutrophil count， C-reactive protein （CRP）， and erythrocyte sedimentation rate （ESR）； cost-effectiveness indicators： antibiotic infusion cost （as a single hospitalization expense）； and nursing workload： infusion distance plus needle removal distance. Statistical analyses included logistic regression and the Mann-Whitney U test. Results The overall incidence of prosthetic joint infection （PJI） at 12 months postoperatively was low. The PJI rates in the single-dose and multiple-dose groups were 1.5% （15/972） and 1.3% （13/976）， respectively， with no statistically significant difference （OR = 1.039， 95%CI： 0.927 ~ 1.164， P = 0.512）. Subgroup analysis results： For hip arthroplasty patients using cefuroxime sodium， inflammatory markers （WBC， neutrophils， CRP， ESR） showed statistically significant differences at various time points within each group （P < 0.05）， but no statistically significant intergroup differences were observed （P > 0.05）. For knee arthroplasty patients using cefazolin sodium， inflammatory markers （WBC， neutrophils， CRP， ESR） showed statistically significant differences at various time points within each group （P < 0.05）. The intergroup difference for CRP was not comparable （P < 0.05）， while no statistically significant intergroup differences were found for the remaining markers （P > 0.05）. For knee arthroplasty patients using cefuroxime sodium， inflammatory markers （WBC， neutrophils， CRP， ESR） showed statistically significant differences at various time points within each group （P < 0.05）. The intergroup difference for ESR was not comparable （P < 0.05）， while no statistically significant intergroup differences were observed for the remaining markers （P > 0.05）. Cost-effectiveness analysis： The median antibiotic cost in the single-dose group was significantly lower than that in the multiple-dose group （74.13 RMB vs. 164.16 RMB， Z = -39.090， P < 0.001）. The nursing workload （infusion distance + needle removal distance） was reduced by a median of 67.1% （298.4 meters vs. 907.8 meters， Z = -37.536， P < 0.001）. Conclusions The single-dose antibiotic regimen is comparable to the multiple-dose regimen in preventing infections， while significantly reducing medical costs （by 55%） and nursing workload （by 67%）. Its clinical adoption is recommended. This study is a single-center retrospective investigation， and future multi-center prospective studies are warranted for further validation.