The first paleoseismologic data from the San Cayetano fault, a major reverse fault that extends along the northern edge of the Ventura Basin northwest of Los Angeles, reveal that the most recent event on the eastern part of the fault generated at least 4.3 m of surface slip. Age determinations from detrital charcoal recovered from the faulted section indicate that this surface rupture occurred after A.D. 1660; the faulted deposits are overlain by unfaulted historical alluvium containing abundant metal fragments and a leather glove. Comparison of the large surface slip in this event with data from other earthquakes indicates that the most recent eastern San Cayetano surface rupture was larger than Mw 7 and was probably of the order of magnitude 7.5—much larger than any earthquakes that have occurred on Los Angeles metropolitan region faults during the past 150 yr. Such a large event almost certainly would have been recorded had it occurred during the historical period, even if it had occurred during the earliest part of the historical era between ca. A.D. 1780 and 1850. Although this surface rupture could have occurred during the century immediately preceding the historic era, the location and large size of the event lead us to suggest that the trench exposed evidence for the damaging earthquake of 21 December 1812. Whether the most recent surface rupture on the eastern San Cayetano fault was the 21 December 1812 event, these paleoseismologic data add to a growing body of evidence that shows that large earthquakes have occurred on faults within and adjacent to the Los Angeles metropolitan region, reemphasizing the need to include such large events on urban faults in future seismic hazard analyses of the region.