Upcoming CO2 legislation in Europe is driving heavy-duty vehicle manufacturers to develop highly efficient engines more than ever before. Further improvements to conventional diesel combustion, or adopting the reactivity controlled compression ignition concept are both plausible strategies to comply with mandated targets. This work compares these two combustion regimes by performing an optimization on both using Design of Experiments. The tests are conducted on a heavy-duty, single-cylinder engine fueled with either only diesel, or a combination of diesel and gasoline. Analysis of variance is used to reveal the most influential operating parameters with respect to indicated efficiency. Attention is also directed towards the distribution of fuel energy to quantify individual loss channels. A load-speed combination typical for highway cruising is selected given its substantial contribution to the total fuel consumption of long haul trucks. Experiments show that when the intake manifold pressure is limited to levels that are similar to contemporary turbocharger capabilities, the conventional diesel combustion regime outperforms the dual fuel mode. Yet, the latter displays superior low levels of nitrogen oxides. Suboptimal combustion phasing was identified as main cause for this lower efficiency. By leaving the intake manifold pressure unrestricted, reactivity controlled compression ignition surpasses conventional diesel combustion regarding both the emissions of nitrogen oxides and indicated efficiency.