The purpose of the present study was to determine whether surgical intervention with open reduction internal fixation (ORIF) or primary arthrodesis (PA) for Lisfranc injuries is more cost effective. We conducted a formal cost-effectiveness analysis using a Markov model and decision tree to explore the healthcare costs and health outcomes associated with a scenario of ORIF versus PA for 45 years postoperatively. The outcomes assessed included long-term costs, quality-adjusted life-years (QALYs), and incremental cost per QALY gained. The costs were evaluated from the healthcare system perspective and are expressed in U.S. dollars at a 2017 price base. ORIF was always associated with greater costs compared with PA and was less effective in the long term. When calculating the cost required to gain 1 additional QALY, the PA group cost $1429/QALY and the ORIF group cost $3958/QALY. The group undergoing PA overall spent, on average, $43,192 less than the ORIF group, and PA was overall a more effective technique. Strong dominance compared with ORIF was demonstrated in multiple scenarios, and the model's conclusions were unchanged in the sensitivity analysis even after varying the key assumptions. ORIF failed to show functional or financial benefits. In conclusion, from a healthcare system's standpoint, PA would clearly be the preferred treatment strategy for predominantly ligamentous Lisfranc injuries and dislocations.