In a heat-integrated crude oil distillation system with an atmospheric distillation unit and heat recovery system, pre-separation units (a preflash or prefractionator) can help to reduce the furnace duty and improve energy efficiency of the system. The high operating and equipment cost and complexity of the system motivate the development of systematic approaches for optimal design. The approach needs to consider both design of the distillation unit and the optimisation of operating conditions in the system, including those related to the preflash unit. This work introduces an optimisation-based methodology for the design of crude oil distillation systems with preflash units. The objective is to minimise fired heat demand of the system while meeting product quality and yield specifications, where pinch analysis is applied to estimate minimum utility requirements. A stochastic optimisation algorithm (a genetic algorithm) is applied to identify the feed location of the flash vapour, the number of stages in each column section and the optimal operating conditions. Operational optimisation variables include pump-around duties and temperature drops, stripping steam flow rates, the column feed temperature, reflux ratio and preflash temperature. The approach is based on the simulation–optimisation technique of Caballero et al. (2005). In order to facilitate integration of modelling and optimisation, an interface between MatLab R2016a and Aspen HYSYS v8.8 is employed. A case study illustrates how the design methodology proposed in this work can reduce demand for fired heating.