Drivers and passengers who drown while trapped in their vehicles or exiting from vehicles account for most flood-related deaths in the United States, yet little has been known about crash circumstances or risk factors for flood-related motor vehicle injury. We conducted a case-control study of all occupants of single-vehicle crashes in flood-affected North Carolina counties where drowning deaths occurred on 15, 16, and 17 September 1999 (the days before, during, and after landfall of Hurricane Floyd); a descriptive study of deaths using medical examiner records; and a survey of proxy respondents for persons who drowned. In 66 crashes vehicles hit puddles and went off the road, went off the road in rain, drove into water and stalled, hit trees in the road, or drove into collapsed sections of road; 19 of these vehicles were partially or fully submerged in water. Occupants of submerged vehicles were more likely to have drowned if their vehicles were fully submerged (14 of 19, 73.7%) than if their vehicles were partly submerged (0 of 8, 0%). According to proxy informants, most of the persons who drowned were familiar with the roads traveled during the study period, and all 16 had received severe weather warnings. Motor vehicle occupants in weather-related crashes are more likely to drown if their vehicles are submerged or swept away. Vehicle submersion may often be a consequence of deliberately driving into flooded roadways. However, in flood-affected areas, crashes and injuries may also occur when motorists encounter flooded roadways unexpectedly.