High-density polyethylene (HDPE) is widely used as the main material in the film, pipe, and container industries. To meet the different market requirements, a process is expected to be capable of producing a number of grades of HDPE products using the same equipment. Given that molecular weight distribution process operating conditions with different specifications on MWD is highly significant. The current study develops an approach for the optimization of an industrial HDPE slurry process with target MWD. To exploit fully the advantages of nonlinear programming (NLP) algorithms, a complete equation-oriented (EO) model including rigorous kinetic mechanism, thermodynamics, and MWD calculation is first established. Model validation is conducted with real plant data to show the good accuracy of calculated MWD. The good performance of the EO model in convergence is also demonstrated through simulations. On the basis of the EO model, productivity optimization with a specified MWD as a constraint is proposed and solved by using an efficient simultaneous approach. Case studies of biomodal and unimodal MWD curves for the process with two reactors in a series are presented. Further study shows that the optimization also works for a different process configuration wit h reactors in parallel. This systematic method shows good potential to optimize the productivity for different product quality demands.