We describe the clinical patterns and case-fatality rate associated with severe Rift Valley fever (RVF) in patients who were admitted to the Gizan regional referral hospital during an outbreak of RVF in Saudi Arabia from September through November 2000. A total of 165 consecutive patients (136 men and 29 women) were prospectively studied; all were identified according to a strict case definition, were confirmed to have RVF by serologic testing, and were treated according to a predetermined protocol. The major clinical characteristics of RVF included a high frequency of hepatocellular failure in 124 patients (75.2%), acute renal failure in 68 patients (41.2%), and hemorrhagic manifestations in 32 patients (19.4%). Sixteen patients had retinitis and 7 patients had meningoencephalitis as late complications in the course of the disease. A total of 56 patients (33.9%) died. Hepatorenal failure, shock, and severe anemia were major factors associated with patient death.