Experiments were conducted on a large bore, medium speed, single cylinder, diesel engine to investigate operation with substitution ratio of natural gas (NG) varying from 0% to 93% by energy. In a previous study by the same group, these data were used to validate an analytical methodology for predicting performance and emissions under a broad spectrum of energy substitution ratios. For this paper, these experimental data are further analyzed to better understand the performance and combustion behavior under NG substitution ratios of 0%, 60%, and 93%. These results show that by transitioning from diesel-only to 60% dual-fuel (DF) (60% NG substitution ratio), an improvement in the NOx-efficiency trade-off was observed that represented a ∼3% improvement in indicated efficiency at constant NOx. Further, the transition from 60% DF to 93% DF (93% NG substitution ratio) resulted in additional efficiency improvement with a simultaneous reduction in NOx emissions. The data suggest that this improvement can be attributed to the premixed nature of the high substitution ratio case. Furthermore, the results show that high cycle-to-cycle variation was observed for some 93% DF combustion tests. Further analysis, along with diesel injection rate measurements, shows that the observed extreme sensitivity of the combustion event can be attributed to critical parameters such as diesel fuel quantity and injection timing. These results suggest a better understanding of the relative importance of combustion system components and operating conditions in controlling cycle-to-cycle variation of combustion process.