Objectives The aim of this study was to evaluate the efficacy and tolerability of a 4% tetrasodium EDTA (tEDTA) infusion protocol in the subcutaneous ureteral bypass (SUB) devices of cats with intraluminal obstruction at a veterinary teaching hospital between July 2017 and April 2020. Methods This was a retrospective controlled study. Cats with an obstructed SUB device underwent a 4% tEDTA infusion protocol. Obstruction of the device was diagnosed based on renal pelvic dilation, dilatation of the ureter, mineralized material within the device (cystostomy or nephrostomy catheters) seen on ultrasound, the absence of visible bubbles within the renal pelvis and/or urinary bladder following ultrasound-guided flushing of the device with saline. Results A total of 16 tEDTA infusion protocols were performed in 14 cats. The infusion protocol was considered successful in 11/16 SUB devices (68.8%). Six devices (n = 6/11; 54.5%) had recurrence of obstruction with a median time of 87 days. One or more episodes of self-limiting pollakiuria and/or hematuria following infusion was seen in eight patients (n = 8/14; 57.1%). Conclusions and relevance Infusions of 4% tEDTA successfully relieved intraluminal obstruction in patients with occluded SUB devices; however, the recurrence of obstruction was common. Additional studies evaluating case selection and optimal protocols are warranted.