Background: We have conducted a prospective cohort study with the aim of comparing operative time, intraoperative blood loss, and radiologic and clinical outcomes between imageless (NAVIO) and image-based (MAKO) robot-assisted unicompartmental knee arthroplasty (UKA) for medial compartment osteoarthritis (OA) of the knee. Methods: A total of 33 patients with medial compartment OA of the knee were prospectively allocated on alternate operative days of their surgery to MAKO (16 patients) or NAVIO (17 patients) robot-assisted UKA. The primary outcome (Knee Society Score [KSS] and Knee Functional Score [KFS]) and the secondary outcomes (intraoperative time of seven steps [registration of hip and ankle, femur and tibia, ligament tension, implant planning, preparation femur, tibia and trial implant], component alignment [coronal and sagittal of femur, tibia implant], blood loss, complications, and revision at 1 year after surgery) were compared between two groups. Statistical significance was set at P < 0.05. Results: Mean KSS measured at baseline and 1 year were, respectively, 70.3 (5.6) and 96.9 (5.7) in the NAVIO group and 72.3 (4.5) and 94.7 (10.01) in the MAKO group. Mean KFS measured at baseline and 1 year were, respectively, 95.5 (7.9) and 99.9 (0.25) in the NAVIO group and 67.3 (7.8) and 99.5 (1.2) in the MAKO group. There were no significant differences for KFS and KSS outcomes (P = 0.203 and P = 0.457, respectively) between the NAVIO and MAKO groups. Mean operative time and blood loss in the NAVIO versus MAKO robot-assisted UKA groups were 98 min versus 82.5 min and 136.3 ml versus 80 ml, respectively, and these differences were statistically significant. In the MAKO group, the intraoperative time was statistically significantly shorter in registration of hip and ankle center, femur and tibia, femur preparation, and trial implantation compared with the NAVIO group. There were no significant differences of component alignment and radiologic alignment at 1 year between the two groups. No perioperative or delayed complications (infection, periprosthetic fracture, thromboembolism, and compromised wound healing) and revisions were reported in either group. Conclusions This study demonstrated that two robotic systems showed no difference in clinical outcomes at 1 year and radiologic alignment of implants, whereas operative time and intraoperative blood loss were found to be less in MAKO robot-assisted UKA.