The ability to switch between different lifestyles allows bacterial pathogens to thrive in diverse ecological niches1,2. However, a molecular understanding of their lifestyle changes within the human host is lacking. Here, by directly examining bacterial gene expression in human-derived samples, we discover a gene that orchestrates the transition between chronic and acute infection in the opportunistic pathogenPseudomonas aeruginosa. The expression level of this gene, here namedsicX, is the highest of theP.aeruginosagenes expressed in human chronic wound and cystic fibrosis infections, but it is expressed at extremely low levels during standard laboratory growth. We show thatsicXencodes a small RNA that is strongly induced by low-oxygen conditions and post-transcriptionally regulates anaerobic ubiquinone biosynthesis. Deletion ofsicXcausesP.aeruginosato switch from a chronic to an acute lifestyle in multiple mammalian models of infection. Notably,sicXis also a biomarker for this chronic-to-acute transition, as it is the most downregulated gene when a chronic infection is dispersed to cause acute septicaemia. This work solves a decades-old question regarding the molecular basis underlying the chronic-to-acute switch inP.aeruginosaand suggests oxygen as a primary environmental driver of acute lethality.