Energetic nanoparticles are promising fuel additives due to their high specific surface area, high energy content, and catalytic capability. Novel amorphous reactive mixed-metal nanopowders (RMNPs) containing Ti, Al, and B, synthesized via a sonochemical reaction, have been developed at the Naval Research Laboratory. These materials have higher energy content than commercial nano-aluminum (nano-Al), making them potentially useful as energy-boosting fuel components. This work examines combustion of RMNPs in a single-cylinder diesel engine (Yanmar L48V). Fuel formulations included up to 4 wt % RMNPs suspended in JP-5, and equivalent nano-Al suspensions for comparison. Although the effects were small, both nano-Al and RMNPs resulted in shorter ignition delays, retarded peak pressure locations, decreased maximum heat release rates, and increased burn durations. A similar but larger engine (Yanmar L100V) was used to examine fuel consumption and emissions for a suspension of 8 wt % RMNPs in JP-5 (and 8 wt % nano-Al for comparison). The engine was operated as a genset under constant load with nominal gross indicated mean effective pressure of 6.5 bar. Unfortunately, the RMNP suspension led to deposits on the injector tip around the orifices, while nano-Al suspensions led to clogging in the fuel reservoir and subsequent engine stall. Nevertheless, fuel consumption rate was 17% lower for the nano-Al suspension compared to baseline JP-5 for the time period prior to stall, which demonstrates the potential value of reactive metal powder additives in boosting volumetric energy density of hydrocarbon fuels.