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The pneumonic influenza pandemic was, on a world scale, the deadliest of the entire 20th century. Between spring 1918 and April 1919, it raged in Portugal in three successive waves, with an irregular and unusual virulence, which were marked by an intense scientific debate. It happened at a time when the etiologic agent of influenza (the influenza virus) had not been identified and the antibiotics had not been discovered, launching numerous prophylactic and therapeutic challenges to national and international health authorities. In this article, some of these aspects are approached, based on medical literature of that period and the research developed later, trying to discuss some of the biological characteristics of the epidemic that may explain, in part, the seriousness of this epidemic phenomenon.