Increasing the lipid production rate stands as one of the challenges for achieving economic feasibility of microalgal biorefinery. Various bioreactor operation strategies have been considered for culturing microalgae, including batch, continuous, fed-batch, semi-batch, and two-stage operations. However, since the previous studies used different experimental criteria, it is hard to draw a conclusion about their relative performances. Motivated by this, the present study compares lipid productivity performances and capital expenditures of the various operation strategies after their operating conditions are optimized. The optimal condition for each strategy is determined by performing a model-based optimization to maximize lipid productivity, which is a good indicator of the overall economics. The two-stage operation with continuous-batch serial connection (w/ stress condition) and the semi-batch operation (w/o stress condition) show outstanding performance compared to the other types of operation. Also, start-up, initial cell concentration, and chemical consumption, which are critical factors in large-scale cultivation, are analyzed. (C) 2018 Elsevier Ltd. All rights reserved.