This paper develops a new advanced process control (APC) system for the multiple-input multiple-output (MIMO) semiconductor processes using the partial least squares (PLS) technique to provide the run-to-run control with the virtual metrology data, via the gradual mode or the rapid mode depending on the current system status, in order to deal with metrology delays and compensate for different types of system disturbances. First, we present a controller called the PLS-MIMO double exponentially weighted moving average (PLS-MIMO DEWMA) controller. It employs the PLS method as the model building/estimation technique to help the DEWMA controller generate more consistent and robust control outputs than purely using the conventional DEWMA controller. To cope with metrology delays, the proposed APC system uses the pre-processing metrology data to build up the virtual metrology (VM) system that can provide the estimated process outputs for the PLS-MIMO DEWMA controller. Lastly, the Fault Detection (FD) system is added based upon the principal components of the PLS modeling outcomes, which supplies the process status for the VM mechanism and the PLS-MIMO DEWMA controller as to how the process faults are responded. Two scenarios of the simulation study are conducted to illustrate the APC system proposed in this paper. (c) 2013 Elsevier Ltd. All rights reserved.