This paper presents an experimental and numerical investigation of the autoignition of ethanol blended with several primary reference fuels (PRFs) and toluene reference fuels (TRFs) in a Cooperative Fuel Research (CFR) engine. Autoigniting, in-cylinder pressure traces are acquired under standard research octane number (RON) conditions. Equivalent, non-autoignitiing traces are obtained by adding a small amount of tetraethyl lead (TEL) to each fuel to suppress knock, and these are used to calibrate a two-zone engine model of autoignition. The simulated autoignition timing of the PRFs without ethanol, TRFs without ethanol, and ethanol/PRF and ethanol/TRF blends are then compared to those measured in the engine. These results suggest that the incorporation of residual NO significantly improves the agreement between simulations and experiment for all cases with no or low ethanol content. Ethanol also appears to suppress the low-temperature activity of n-heptane. Both of these results are consistent with previous, more fundamental studies. However, close agreement between the simulated and measured autoignition timing across all fuel blends is not observed. Thus, the modeling does not comprehensively explain the significant synergism and antagonism observed in a recent study of the octane numbers of these fuels (Foong, T. M.; Morganti, K. J.; Brear, M. J.; da Silva, G.; Yang, Y.; Dryer, F. L. The octane numbers of ethanol blended with gasoline and its surrogates.