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 also fuel economy and emission 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) and regression analysis are used to investigate the influence of a variety of operating conditions on optimal post-injection scheduling. The study targets emissions of soot and NOx, as well as fuel economy. Experiments are conducted on a heavy-duty compression ignition engine at an intermediate load and two common engine speeds. Regression analysis shows that the eventual decrease in engine-out soot heavily depends on initial oxygen availability in both load-speed combinations. This observation supports the suggestion that enhanced late-cycle mixing of fuel and oxidizer is an important contributor to observed soot reductions. Furthermore, simultaneous improvements to NOx and fuel economy with little or no penalty on soot are obtained for particular injection scheduling. At higher engine speed, emissions and fuel economy were found to exhibit a greater sensitivity to timing of the post-injection. Notably exhaust gas recirculation (EGR) proved to be an effective parameter in the overall optimization of existing trade-offs, which strengthens similar claims from previous work. Eventually, several general guidelines for post-injection scheduling are postulated.