In vitro active shoulder motion simulation can provide improved understanding of shoulder biomechanics; however, accurate simulators using advanced control theory have not been developed. Therefore, our objective was to develop and evaluate a simulator which uses real-time kinematic feedback and closed loop proportional integral differential (PID) control to produce motion. The simulator’s ability to investigate a clinically relevant variable—namely muscle loading changes resulting from reverse total shoulder arthroplasty (RTSA)—was evaluated and compared to previous findings to further demonstrate its efficacy. Motion control of cadaveric shoulders was achieved by applying continuously variable forces to seven muscle groups. Muscle forces controlling each of the three glenohumeral rotational degrees of freedom (DOF) were modulated using three independent PID controllers running in parallel, each using measured Euler angles as their process variable. Each PID controller was configured and tuned to control the loading of a set of muscles which, from previous in vivo investigations, were found to be primarily responsible for movement in the PID’s DOF. The simulator’s ability to follow setpoint profiles for abduction, axial rotation, and horizontal extension was assessed using root mean squared error (RMSE) and average standard deviation (ASD) for multiple levels of arm mass replacement. A specimen was then implanted with an RTSA, and the effect of joint lateralization (0, 5, 10 mm) on the total deltoid force required to produce motion was assessed. Maximum profiling error was <2.1 deg for abduction and 2.2 deg for horizontal extension with RMSE of <1 deg. The nonprofiled DOF were maintained to within 5.0 deg with RMSE <1.0 deg. Repeatability was high, with ASDs of <0.31 deg. RMSE and ASD were similar for all levels of arm mass replacement (0.73–1.04 and 0.14–0.22 deg). Lateralizing the joint’s center of rotation (CoR) increased total deltoid force by up to 8.5% body weight with the maximum early in abduction. This simulator, which is the first to use closed loop control, accurately controls the shoulder’s three rotational DOF with high repeatability, and produces results that are in agreement with previous investigations. This simulator’s improved performance, in comparison to others, increases the statistical power of its findings and thus its ability to provide new biomechanical insights.