The maritime transportation of goods and passengers appears to be in the area of conflict between economical and punctual operation and the severe maritime emission regulations. As a consequence of the global warming more strict maritime emission regulations are globally in force or will become applicable in the near future (NOx emission control areas in North America and Baltic & North Sea from 2021). The tough competition puts economic pressure on the maritime transport industry. Therefore, the demand for efficient and mostly environmental neutral propulsion systems, which meet the environmental legislations and minimizes the cargo costs is immense. Medium speed dual fuel engines are in accordance with the strict maritime emissions legislation IMO Tier III. They do not require any exhaust gas aftertreatment, show economic benefit due to the reduced fuel expenses and allow fuel flexibility. The cylinder cut-out is investigated for a medium speed dual fuel engine based on the predictive 1D GT-Power simulation model. Low and high pressure indication, NO emissions, and knock behaviour are validated against test bench data. Different static cut-out and skip firing operation sequences are simulated and assessed. The developed optimization workflow is set up in Optimus. The selected metaheuristic optimization algorithm varies the cut-out sequences and the equivalence ratio to optimize the engine efficiency under consideration of NO emission and knock limits. The optimization is conducted for discrete engine operation points in a load range from 10% to more than 40%. The optimization predicts a significant increase of the brake efficiency and reduced methane slip at low and part load operation. This depends on an increased turbocharger efficiency, reduced pumping work, richer combustion and higher indicated mean effective pressures of the fired cylinders which leads to an improved combustion (shifted from diffusion to premix) and engine efficiency without exceeding the NO emission limit.