Background: Venous thromboembolism (VTE) has been reported in approximately 5-7% of patients undergoing radical cystectomy (RC). While extended-duration pharmacologic prophylaxis (EDPP) has been investigated following surgery for a variety of malignancies, limited data exist in bladder cancer. Herein, we evaluated the efficacy and safety of EDPP after RC. Methods: We instituted a change in our clinical practice beginning in May 2014 such that patients undergoing RC were prescribed 30 days of enoxaparin at discharge. We recorded symptomatic VTE and lymphocele rates within 30 days of RC among patients treated from 5/14-6/15, and compared these outcomes to the cohort of all patients who underwent RC at our institution in the year prior to EDPP implementation. Patients in both groups received subcutaneous unfractionated heparin and mechanical prophylaxis during hospitalization. Patients with a history of VTE prior to surgery (n = 24) were excluded from study. Unadjusted descriptive statistics and univariate analyses were performed using the Pearson or Fisher chi-square test for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: In total, 58 patients who received EDPP and 82 patients who had not received EDPP after RC were included for analysis. Baseline clinicopathologic demographics were similar between the cohorts. We found that only 1 patient (1.9%) discharged with EDPP was diagnosed with a VTE within 30 days of RC, compared to 5 (6.1%) who had not received EDPP. Mean time to VTE was 18.0 days after RC (range 9-28 days). Events consisted of DVT alone (n = 2), DVT and PE (n = 2), and PE alone (n = 2). The odds ratio for VTE in the absence of EDPP was 3.31 (95% CI 0.38, 29.2). Overall, 3 patients developed a symptomatic lymphocele within 30 days of RC: 1 (1.9%) who received EDPP and 2 (2.4%) who had not (p = 0.84). No patient in either cohort was rehospitalized for bleeding complications. Conclusions: Our initial experience suggests that EDPP was associated with a lower rate of VTE following RC, and does not increase the risks of bleeding or symptomatic lymphocele. Future evaluation in a larger-scale prospective clinical trial setting is needed to confirm the benefit of EDPP in RC patients.