Objectives: To evaluate the economic impact of the combined effect of minimally invasive surgery (MIS) and a multimodal analgesia regimen (Total Joint Regional Anesthesia [TJRA] Clinical Pathway) on the estimated direct medical costs of patients undergoing total knee arthorplasty (TKA) or total hip arthroplasty (THA). Patients and Methods: A retrospective cohort, cost comparison study from the hospital prospective was performed on Mayo Clinic patients (n=37) undergoing MIS TKA or THA using the TJRA Clinical Pathway. Study patients were matched 1:1 with historical controls undergoing similar procedures using traditional surgical and anesthetic (non- TJRA) techniques. Hospital-based direct costs were collected for each patient and analyzed in standardized inflation-adjusted constant dollars using cost-to-charge ratios, wage indexes, and physician services valued using Medicare reimbursement rates. The estimated mean direct hospital costs were compared between groups and a subgroup analysis was performed based upon ASA physical status classification. Results: The estimated mean direct medical costs were significantly reduced among MIS with TJRA patients compared to controls (cost difference: $4582; 95% CI $3299-$5864; P <.001). A significant reduction was found in both the hospital-based (Medicare Part A) costs and the physician-based (Medicare Part B) costs. Conclusions: The combined use of minimally invasive surgical (MIS) approaches and a multimodal analgesic regimen (TJRA Clinical Pathway) in patients undergoing lower extremity joint replacement provides a significant reduction in the estimated mean medical costs. A significant reduction occurs in both the hospital based (Medicare Part A) and the physician based (Medicare Part B) costs. In subgroup analysis, the greatest difference was found among the patients with significant comorbidities (ASA III-IV patients).