Ocean Thermal Energy Conversion (OTEC) produces electricity using the temperature difference between warm surface and cold deep-sea water. OTEC systems in literature only limitedly consider seasonal seawater temperature variations and thus might not be adequately sized for off-design conditions. This potentially leads to techno-economically sub-optimal design choices. This paper sheds light on which design approach yields the most economically feasible OTEC system considering off-design conditions with 19 years of seawater temperature data in 3-h time steps. We find that systems sized for worst-case thermal resources yield the highest and steadiest electricity production. If seawater temperature variations are moderate, these systems also perform best economically in terms of Levelized Cost of Electricity (LCOE). We demonstrate our model for a 136 MWgross plant in Ende, Indonesia, with an LCOE of 15.12 US¢(2021)/kWh against a local electricity tariff of 15.77 US¢(2021)/kWh. The model is validated for different cost assumptions, system sizes, and temperature profiles to be useful globally. We give recommendations to curb costs and to move large-scale OTEC closer to today’s state of the art, e.g. by using multiple smaller seawater pipes instead of few large pipes. The model is useful to prove OTEC’s global economic feasibility and to promote the technology’s commercialisation.