Opposed-piston, two-stroke engines reveal degrees of freedom that make them excellent candidates for next generation, highly efficient internal combustion engines for hybrid electric vehicles and power systems. This article reports simulation results that explore the influence of key control and geometrical parameters, specifically crankshaft phasing and intake and exhaust port height-to-stroke ratios, in obtaining best thermal efficiency. A model of a 0.75 L, single-cylinder opposed-piston two-stroke engine is exercised to predict fuel consumption as engine speed, load, crankshaft phasing, intake and exhaust port height-to-stroke ratios, and stoichiometry are varied for medium-duty truck and range extender applications. Under stoichiometric operation, optimal crankshaft phasing is seen at 0–5°, lower than reported in the literature. If stoichiometric operation is not mandated, best fuel consumption is achieved at an air-to-fuel equivalence ratio λ = 1.25 and 5–10° crankshaft phase angle, enabling a ~10 g/kWh (~4%) improvement in average brake-specific fuel consumption across medium-duty truck operating points. In range extender form, the engine provides 30 kW output power in accordance with a survey of range extender engines. In this role, there is a clear distinction between low-speed, high-load operation and vice versa. The decision as to which is more appropriate would be based on minimizing total owning and operating cost, itself a trade-off between better thermal efficiency (and thus lower fuel cost) and greater durability.