BACKGROUND: The current worst-case scenario for pandemic influenza planning is based on the catastrophic 1918-1919 pandemic. In this article, we examine the strength of cross-protection between successive waves of the 1918-1919 pandemic, which has remained a long-standing issue of debate. METHOD: We studied monthly hospitalization and mortality rates for respiratory illness in 37 army camps, as well as the rates of repeated episodes of influenza infection during January-December 1918 in 8 military and civilian settings in the United States and Britain. RESULTS: A first wave of respiratory illness occurred in US Army camps during March-May 1918 and in Britain during May-June, followed by a lethal second wave in the fall. The first wave was characterized by high morbidity but had a lower fatality rate than the second wave (1.1% vs. 4.7% among hospitalized soldiers; P < .001). Based on repeated illness data, the first wave provided 35%-94% protection against clinical illness during the second wave and 56%-89% protection against death (P < .001). CONCLUSION: Exposure to influenza in the spring and summer of 1918 provided mortality and morbidity protection during the fall pandemic wave. The intensity of the first wave may have differed across US cities and countries and may partly explain geographical variation in pandemic mortality rates in the fall. Pandemic preparedness plans should consider that immune protection could be naturally acquired during a first wave of mild influenza illnesses.