In this paper, the optimal design of two-phase horizontal knockout drums is addressed. An optimization model is developed that predicts separator performance subject to nonlinear design constraints. The proposed model gives rise to a nonconvex, nonlinear problem that often causes convergence difficulties for standard local optimization techniques. We propose an optimal solution procedure based on a search parametric approach. Extensive numerical simulations on a case study are used to illustrate the proposed heuristic procedure that yields to a minimal cost design of knockout drums. Results of in-depth analysis aimed to characterize liquid-gas separation in horizontal knockout drums are also presented.