Background Venous thromboembolism (VTE) and the subsequent development of pulmonary embolism (PE) is a major cause of post-operative mortality in total knee arthroplasty (TKA). We evaluated whether the addition of an ultrasound-guided femoral nerve block with general anesthesia affected the incidence in the development of VTE following TKA. Methods This was a retrospective non-randomized comparative study with patients assigned to groups based on the surgery date (pre-femoral nerve block versus post-femoral nerve block periods). All anesthesia and medical records of the patients who had undergone computer-navigated TKA in our facility between January 2009 and March 2010 were retrospectively reviewed. Results Forty patients were identified; 15 patients underwent computer-navigated TKA under general anesthesia alone (Group G) and 25 patients underwent surgery under general anesthesia combined with ultrasound-guided femoral nerve block (Group F). The incidence of development of VTE post-operatively was significantly lower in Group F (P = 0.037). Logistic regression analysis identified the use of a femoral nerve block as the most significant variable correlating with the incidence of post-operative development of VTE, and the odds ratio for VTE development in Group G was 3.12 (95% CI, 0.57-20.56). Conclusions We suggest the possibility that the addition of a femoral nerve block on general anesthesia may reduce the incidence of the development of VTE following TKA.