Introduction: The management of urinary clot retention and hematuria involves manual irrigation with sterile water or normal saline via a Foley catheter followed by continuous bladder irrigation. Irrigation may become difficult because of the formation of dense blood clots. Tissue plasminogen activator (t-PA/Alteplase) may be a useful pharmacological agent to improve the efficacy of manual irrigation of large, dense clots. The goal of the current study was to compare t-PA to sterile water for clot irrigation in an in vitro model. Materials and Methods: In vitro models of clot retention were created using 500-cc urinary leg bags each filled with 80 cc of unpreserved whole blood from a healthy volunteer. Each model was incubated at 25°C for 24 hours to allow clot formation. Four models each with 25mL solution of t-PA at concentrations of 2, 1, 0.5, and 0.25°mg/mL were evaluated and compared to a control (25°mL sterile water). Models were instilled with solution (t-PA or control) and incubated for 30 minutes at 37°C, and then irrigated with sterile water via 18F Foley by a blinded investigator. Three separate experiments were conducted, and statistical analysis was performed comparing various irrigation parameters. Results: Clot evacuation with 25°mL of t-PA at a concentration of 2°mg/mL (50°mg) was significantly easier (p≤ 0.05) and faster (p<0.05) than the sterile water control. The mean time for clot evacuation in this model was 2.7 minutes for t-PA solution 2mg/mL versus 7.3 minutes for the control (p<0.05). Compared to the control, irrigation with t-PA solution 2mg/mL also required less irrigant (180mL vs. 500mL) (p<0.05) for complete evacuation. There was a similar trend in efficacy for the lower doses of t-PA, but this was not statistically significant. Conclusion: In this in vitro study, a single 25mL instillation of t-PA solution 2mg/mL is significantly better than sterile water alone for clot evacuation. In vivo animal studies are pending.