A multivariable model predictive control (MPC) algorithm is developed for the control and operation of a rapid pressure swing adsorption (RPSA)‐based medical oxygen concentrator. The novelty of the approach is the use of all four step durations in the RPSA cycle as independent manipulated variables in a truly multivariable context. The RPSA has a complex, cyclic, nonlinear multivariable operation that requires feedback control, and MPC provides a suitable framework for controlling such a multivariable system. The multivariable MPC presented here uses a quadratic optimization program with integral action and a linear model identified using subspace system identification techniques. The controller was designed and tested in simulation using a complex, highly coupled, nonlinear RPSA process model. The model was developed with the least restrictive assumptions compared to those reported in the literature, thereby providing a more realistic representation of the underlying physical phenomena. The resulting MPC effectively tracks set points, rejects realistic process disturbances and is shown to outperform conventional PID control. © 2017 American Institute of Chemical Engineers AIChE J, 64: 1234–1245, 2018