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Post-injection strategies prove to be a valuable option for reducing soot emission, but experimental results often differ from publication to publication. These discrepancies are likely caused by the selected operating conditions and engine hardware in separate studies. Efforts to optimize not only engine-out soot, but simultaneously fuel economy and emissions of nitrogen oxides (NOx) complicate the understanding of post-injection effects even more. Still, the large amount of published work on the topic is gradually forming a consensus. In the current work, a Design-of-Experiments (DoE) procedure and regression analysis are used to investigate the influence of various operating conditions on post-injection scheduling and efficacy. The study targets emission reductions of soot and NOx, as well as fuel economy improvements. Experiments are conducted on a heavy-duty compression ignition engine at three load-speed combinations.