Fuels in the gasoline auto-ignition range (Research Octane Number (RON) > 60) have been demonstrated to be effective alternatives to diesel fuel in compression ignition engines. Such fuels allow more time for mixing with oxygen before combustion starts, owing to longer ignition delay. Moreover, by controlling fuel injection timing, it can be ensured that the in-cylinder mixture is “premixed enough” before combustion occurs to prevent soot formation while remaining “sufficiently inhomogeneous” in order to avoid excessive heat release rates. Gasoline compression ignition (GCI) has the potential to offer diesel-like efficiency at a lower cost and can be achieved with fuels such as low-octane straight run gasoline which require significantly less processing in the refinery compared to today’s fuels.To aid the design and optimization of a compression ignition (CI) combustion system using such fuels, a global sensitivity analysis (GSA) was conducted to understand the relative influence of various design parameters on efficiency, emissions and heat release rate. The design parameters included injection strategies, exhaust gas recirculation (EGR) fraction, temperature and pressure at intake valve closure and injector configuration. These were varied simultaneously to achieve various targets of ignition timing, combustion phasing, overall burn duration, emissions, fuel consumption, peak cylinder pressure and maximum pressure rise rate. The baseline case was a three-dimensional closed-cycle computational fluid dynamics (CFD) simulation with a sector mesh at medium load conditions. Eleven design parameters were considered and ranges of variation were prescribed to each of these. These input variables were perturbed in their respective ranges using the Monte Carlo (MC) method to generate a set of 256 CFD simulations and the targets were calculated from the simulation results. GSA was then applied as a screening tool to identify the input parameters having the most significant impact on each target. The results were further assessed by investigating the impact of individual parameter variations on the targets. Overall, it was demonstrated that GSA can be an effective tool in understanding parameters sensitive to a low temperature combustion concept with novel fuels.