Researchers have discovered a new anti-quorum sensing system (anti-pqs) activity in three “old” FDA-approved drugs originally developed for the treatment of diseases different from Pseudomonas aeruginosa (Pa) infection. The anti-virulence activity of each one of the three drugs was tested against a collection of 100 P. aeruginosa strains isolated from CF patients, having different antibiotic resistance profiles. The interaction of the anti-pqs drugs with antibiotics commonly used in CF therapy was studied in Pa liquid and biofilm cultures. The anti-pqs drugs resulted significantly active against a large percentage of CF strains, even if to different extents, and showed no antagonistic effects toward antibiotics. In particular, multidrug-resistant (MDR) strains seemed to be particularly susceptible to one of these drugs, named Clofoctol. Results based also on toxicity and pharmacokinetic considerations support Clofoctol as the most promising anti-virulence drug for repurposing in CF therapy. However, additional confirmatory studies carried out with a larger number of MDR-Pa CF isolates should be carried out before proceeding with further studies in animal infection models. The final aim is to identify a new “old “ drug suitable to be faster transferred to CF patients.