Our purpose was to assess the effect of workspace configuration on radiation therapists’ (RTs) physical stressors, mental workload (WL), situational awareness (SA), and performance during routine treatment delivery tasks in a simulated environment. Fourteen RTs were randomized to 2 workspace configurations while performing 4 simulated scenarios-current (not ergonomically optimized; n = 7) and enhanced (ergonomically optimized, n = 7). Physical stressors were objectively assessed using a rapid upper limb assessment tool. Mental WL was measured at the end of each simulated scenario subjectively using the NASA Task-Load Index and objectively throughout the scenario using eye-tracking metrics (pupil diameter and blink rate). SA was measured at the end of each simulated scenario subjectively using the situation awareness and review technique. Performance was measured objectively via assessment of time-out compliance, error detection, and procedural compliance. Analysis of variance was used to test the effect of workspace configuration on physical stressors, mental WL, SA, and performance. The enhanced configuration significantly reduced physical stressors (rapid upper limb assessment; P < .01) and resulted in a higher rate of time-out compliance (P = .01) compared with current workspace configuration. No significant effect on other metrics was measured. Our results suggest that an ergonomically designed workspace may minimize physical stressors and improve the performance of RTs.