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Surgical site infections (SSI) remain a significant concern following Type III open fractures. Recent studies have suggested that narrow-spectrum antibiotics like cefazolin (CEZ) may offer comparable efficacy to broader-spectrum combinations in preventing SSI, with potential cost benefits. However, the cost-effectiveness of different prophylactic regimens in Type III open fractures in China has not been comprehensively evaluated. A decision-tree model was constructed for a hypothetical cohort of 1,000 adult patients with Type III open fractures in the Chinese healthcare setting. Six prophylactic antibiotic regimens were compared: cefazolin (CEZ), cefazolin + aminoglycosides (CEZ + AG), piperacillin/tazobactam (PIPC/TAZ), cefotaxime (CTX), ampicillin/sulbactam (ABPC/SBT) and ceftriaxone (CTRX). Transition probabilities and utility values were derived from published clinical studies, while cost data were obtained from the Chinese Volume-Based Procurement (VBP) policy for drug pricing, along with additional expenses incurred due to SSI. Both one-way deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) were conducted to assess the robustness of the findings against variations in key parameters. From the perspective of the Chinese healthcare system, CEZ was identified as the dominant strategy (lowest cost and highest utility). With a total cost of 1,272.47 CNY and a total utility of 0.3425 QALYs, CEZ yielded the highest net monetary benefit (NMB) of 31,524.54 CNY at a willingness-to-pay (WTP) threshold of 95,749 CNY/QALY (1×GDP per capita). In contrast, all other regimens were found to be dominated (associated with higher costs and lower QALYs), resulting in negative incremental cost-effectiveness ratios (ICERs) relative to CEZ. Among these, CTRX was the least efficient strategy, incurring the highest cost (3,864.94 CNY) while yielding the lowest total utility (0.3262 QALYs). Sensitivity analyses confirmed the robustness of these findings, reinforcing CEZ as the dominant and most cost-effective option. This study highlights the cost-effectiveness advantage of CEZ in preventing SSI following Type III open fractures in China. CEZ is the most cost-effective option overall, demonstrating a clear advantage over all other regimens. These findings provide essential insights for guiding antibiotic selection and optimizing healthcare resource allocation in the prevention of surgical infections.