Volatility in crude oil prices and shrinking refinery margins are forcing refiners worldwide to look for the most profitable plant configuration like never before. Robust evaluation techniques for selecting the most profitable layout for a unit in oil refinery have thus become the need of the hour. This work presents an integrated approach for selection of optimum plant layout, with Diesel Hydrotreating (DHT) unit as an example. Models for two different configurations of a 58,000 BPSD DHT unit for the Middle East location - the 'Hot separator layout' and the 'Cold separator layout' - were developed and detailed profitability analysis was performed on net present value (NPV) basis. Effect of variation of economic parameters on NPV was studied through Response surface methodology (RSM) and Box-Behnken design (BBD). Regression analysis was carried out to develop suitable correlation to predict the NPV difference between the two layouts. The NPV difference as per the developed correlation was compared with actual NPV difference calculated for DHT units from four different regions - India, Middle East, US Gulf Coast and South-East Asia. The maximum error was 17.1% (India) and all other errors were less than 9%, substantiating the robustness of the developed model. (C) 2019 Elsevier Ltd. All rights reserved.