In this experimental investigation, we studied the safety and thermal runaway behavior of commercial lithium-ion batteries of type 21700. The different cathode materials NMC, NCA and LFP were compared, as well as high power and high energy cells. After characterization of all relevant components of the batteries to assure comparability, two abuse methods were applied: thermal abuse by the heat-wait-seek test and mechanical abuse by nail penetration, both in an accelerating rate calorimeter. Several critical temperatures and temperature rates, as well as exothermal data, were determined. Furthermore, the grade of destruction, mass loss and, for the thermal abuse scenario, activation energy and enthalpy, were calculated for critical points. It was found that NMC cells reacted first, but NCA cells went into thermal runaway a little earlier than NMC cells. LFP cells reacted, as expected, more slowly and at significantly higher temperatures, making the cell chemistry considerably safer. For mechanical abuse, no thermal runaway was observed for LFP cells, as well as at state of charge (SOC) zero for the other chemistries tested. For thermal abuse, at SOC 0 and SOC 30 for LFP cells and at SOC 0 for the other cell chemistries, no thermal runaway occurred until 350 °C. In this study, the experimental data are provided for further simulation approaches and system safety design.