This paper studies autoignition characteristics and HCCI engine combustion of ketone fuels, which are important constituents of recently discovered fungi-derived biofuels. Two ketone compounds, 2,4-dimethyl-3-pentanone (DMPN) and cyclopentanone (CPN), are systematically investigated in the Sandia HCCI engine, and the results are compared with conventional gasoline and neat ethanol. It is found that CPN has the lowest autoignition reactivity of all the biofuels and gasoline blends tested in this HCCI engine. The combustion timing of CPN is also the most sensitive to intake-temperature (Tin) variations, and it is almost insensitive to intake-pressure (Pin) variations. These characteristics and the overall HCCI performance of CPN are similar to those of ethanol. In contrast, DMPN shows multi-faceted autoignition characteristics. On the one hand, DMPN has strong temperature-sensitivity, even at boosted Pin, which is similar to the low-reactivity ethanol and CPN. On the other hand, DMPN shows much stronger pressure-sensitivity than ethanol and CPN. This pressure-sensitivity reduces the Tin requirement for DMPN as Pin increases, in a manner similar to gasoline, and it allows the same Tin = 60°C for DMPN as for gasoline at Pin = 2.4 bar. At this Pin, DMPN reaches a maximum HCCI load similar to gasoline, ∼ 14 bar IMEP. Unlike gasoline, which requires significant combustion-timing retard to prevent knock at this maximum load, DMPN allows a more advanced combustion timing because its high temperature-sensitivity causes a lower heat release rate. As a result, DMPN yields a higher thermal efficiency than gasoline at comparable loads.