Future projections in global transportation fuel use show a demand shift toward diesel and away from gasoline. At the same time, greenhouse gas regulations will drive higher vehicle fuel efficiency and lower well-to-wheel CO2 production. Naphtha, a contributor to the gasoline stream and requiring less processing at the refinery level, is an attractive candidate to mitigate this demand shift while lowering the overall greenhouse gas impact. This study investigates the combustion and emissions performance of two naphtha fuels (Naphtha 1: RON59 and Naphtha 2: RON69) and one ultra-low sulfur diesel (ULSD) in a model year (MY) 2013, six-cylinder, heavy-duty diesel engine. Engine testing was focused on the heavy-duty supplemental emissions test (SET) “B” speed over a load sweep from 5 to 15 bar BMEP (brake-specific mean pressure). At each operating point, NOx sweeps were conducted over wide ranges. At 10–15 bar BMEP, mixing-controlled combustion dominates the engine combustion process. Under a compression ratio of 18.9, cylinder pressure and temperature at these load conditions are sufficiently high to suppress the reactivity difference between ULSD and the two naphtha fuels. As a result, the three test fuels showed similar ignition delay (ID). Nevertheless, naphtha fuels still exhibited notable soot reduction compared to ULSD. Under mixing-controlled combustion, this is likely due to their lower aromatic content and higher volatility. At 10 bar BMEP, Naphtha 1 generated less soot than Naphtha 2 since it contains less aromatics and is more volatile. When operated at light load, in a less reactive thermal environment, the lower reactivity naphtha fuels lead to longer IDs than ULSD. As a result, the soot benefit of naphtha fuels was enhanced. Utilizing the soot benefit of the naphtha fuels, engine-out NOx was calibrated from the production level of 3–4 g/hp-hr down to 2–2.5 g/hp-hr over the 12 nonidle SET steady-state modes. At this reduced NOx level, naphtha fuels were still able to maintain a soot advantage over ULSD and remain “soot-free” while achieving diesel-equivalent fuel efficiency. Finally, low-temperature combustion (LTC) operation (NOx ≤ 0.2 g/hp-hr and smoke ≤ 0.2 FSN) was achieved with both of the naphtha fuels at 5 bar BMEP through a late injection approach with high injection pressure. Under high exhaust gas recirculation (EGR) dilution, Naphtha 2 showed an appreciably longer ID than Naphtha 1, resulting in a soot reduction benefit.