This paper systematically studied the coupling effect of ambient pressure and tunnel slope on temperature distribution and smoke propagation in full-scale tunnel fires under natural ventilation by FDS. The downstream length (longitudinal length from fire source center to tunnel downstream exit) was also considered. The concept of “height difference of stack effect” was put forward when analyzing the mutual effect of tunnel slope and downstream length on smoke movement. The results show that the maximum smoke temperature beneath the ceiling decreases with the increasing ambient pressure or tunnel slope. The longitudinal smoke temperature decays faster with the decreasing ambient pressure or slope in inclined tunnel. The induced inlet airflow velocity increases with the increasing height difference of stack effect, while decreases with the increasing ambient pressure. And the smoke backlayering length decreases with the increasing height difference of stack effect. Taking heat release rate (HRR), ambient pressure, tunnel slope and downstream length into account, the prediction models of dimensionless induced inlet airflow velocity and smoke backlayering length in inclined tunnel fires at high altitude were developed, which agree well with our and others’ results. The outcomes of current study are great meaningful to fire detection and smoke control in inclined tunnel fires at high altitude. © 2023, The Author(s)