Purpose Our purpose was to investigate interfraction setup error of the immobilization device required to implement transperineal ultrasound compared with the current, standard immobilization device. Patient comfort and radiation therapist (RT) satisfaction were also assessed. Methods and materials Cone beam computed tomography images were acquired before 4069 fractions from 111 patients (control group, n = 56; intervention group, n = 55) were analyzed. The intervention group was immobilized using the Clarity Immobilization System (CIS), comprising a knee rest with autoscan probe kit and transperineal ultrasound probe (n = 55), and control group using a leg immobilizer (LI) (n = 56). Interfraction setup errors were compared for both groups. Weekly questionnaires using a 10-point visual analog scale were administered to both patient groups to measure and compare patient comfort. RT acceptance for both devices was also compared using a survey. Results There was no significant difference in the magnitude of interfraction cone beam computed tomography–derived setup shifts in the lateral and anteroposterior direction between the LI and CIS (P = .878 and .690, respectively). However, a significant difference (P = .003) was observed in the superoinferior direction between the 2 groups of patients. Patient-reported level of comfort and stability demonstrated no significant difference between groups (P = .994 and .132). RT user acceptance measures for the LI and CIS were ease of handling (100% vs 53.7%), storage (100% vs 61.1%), and cleaning of the devices (100% vs 64.8%), respectively. Conclusions The CIS demonstrated stability and reproducibility in prostate treatment setup comparable to LI. The CIS device had no impact on patient comfort; however, RTs indicated a preference for LI over the CIS mainly because of its weight and bulkiness.