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International audience; Two clinical isolates of the opportunist pathogen Pseudomonas aeruginosa named PAO1 and PA14 are commonly studied in research laboratories. Despite being closely related, PA14 exhibits increased virulence compared to PAO1. To determine which players are responsible for the hypervirulence phenotype of the PA14 strain, we elected for a transcriptomic approach through RNA sequencing. We found 2029 genes that are differentially expressed between the two strains, including several genes that are involved with or regulated by Quorum-Sensing (QS), known to control most of the virulence factors in P. aeruginosa. Among them, we chose to focus our study on QslA, an anti-activator of QS whose expression was barely detectable in the PA14 strain according our data. We hypothesized that lack of expression of qslA in PA14 could be responsible for higher QS expression in the PA14 strain, possibly explaining its hyper-virulence phenotype. After confirming Qs lA protein was highly produced in PAO1 but not in the PA14 strain, we provided evidence showing that a PAO1 deletion strain of qslA has faster QS gene expression kinetics compared to PA14. Moreover, known virulence factors activated by QS such as (i) pyocyanin production, (ii) H2-T6SS(Type VI Secretion System) gene expression, and (iii) Xcp-T2SS (Type II Secretion System) machinery production and secretion were all lower in PAO1 compared to PA14 strain, due to higher qslAexpression. However, biofilm formation and cytotoxicity towards macrophages, although increased in PA14 compared to PAO1, were independent of QslA control. Altogether, our findings implicated differential qslA expression as a major determinant of virulence factor expression in P. aeruginos astrains PAO1 and PA14.