High-efficiency, clean-combustion strategies for heavy-duty diesel engines are critical for meeting stringent emissions regulations and reducing the costs of aftertreatment systems that are currently required to meet these regulations. Results from previous constant-volume combustion-vessel experiments using a single jet of fuel under quiescent conditions have shown that mixing-controlled soot-free combustion (i.e., combustion where soot is not produced) is possible with #2 diesel fuel. These experiments employed small injector-orifice diameters (≺ 150 μm) and high fuel-injection pressures (≻ 200 MPa) at top-dead-center (TDC) temperatures and densities that could be achievable in modern heavy-duty diesel engines. The present study examines the feasibility of mixing-controlled low-soot and soot-free combustion strategies using multi-hole injector tips in a 1.72-liter single-cylinder version of a heavy-duty diesel engine that has been modified to provide extensive optical access to the combustion chamber. Indicated-specific emissions, high-speed images of in-cylinder natural luminosity and OH*-radical chemiluminescence, and indicated efficiency measurements were acquired over parametric sweeps of injection pressure, number of injector-tip orifices, quantity of injected fuel, start of combustion, TDC density, TDC temperature, and mixture composition. These measurements indicate that sustaining soot-free combustion over the entire duration of combustion is limited by jet-jet interactions and the re-entrainment of hot combustion products into each fuel jet near its flame lift-off length. Nevertheless, significant reductions in engine-out smoke levels are possible even if soot-free combustion is not sustained.