Background/Objectives: Urinary tract infections (UTIs) caused by multidrug-resistant (MDR) bacteria pose a considerable challenge due to high treatment failure rates and associated healthcare costs. This pioneering study evaluates the effectiveness of personalized autovaccine therapy in managing recurrent UTIs in patients with MDR bacteria, aiming to offer an innovative treatment that reduces antibiotic resistance and hospitalizations. Methods: In this prospective, single-center study, 40 patients with recurrent MDR UTIs received personalized sublingual autovaccines derived from their own bacterial isolates. The study assessed UTI recurrence rates, changes in antibiotic use, and hospitalization days over 12 months. Results: The autovaccine therapy significantly reduced UTI recurrence, with 67.5% of patients experiencing fewer infections. Antibiotic usage decreased by 74.4%, and total hospitalization days annually reduced from 400 to 216. A significant shift was observed from MDR to multi-susceptible bacterial profiles among participants. Conclusions: This study is the first to demonstrate that autovaccine therapy is a safe and effective approach for managing recurrent UTIs caused by MDR bacteria, significantly lowering infection frequency, antibiotic needs, and hospitalization. These findings support integrating autovaccine therapy into standard UTI management to combat antibiotic resistance and lessen healthcare burdens.