Pseudomonas aeruginosa causes chronic lung infections in the airways of cystic fibrosis (CF) patients. Psl is an extracellular polysaccharide expressed by non‐mucoid P. aeruginosa strains, which are believed to be initial colonizers. We hypothesized that Psl protects P. aeruginosa from host defences within the CF lung prior to their conversion to the mucoid phenotype. We discovered that serum opsonization significantly increased the production of reactive oxygen species (ROS) by neutrophils exposed to a psl‐deficient mutant, compared with wild‐type (WT) and Psl overexpressing strains (Psl⁺⁺). Psl‐deficient P. aeruginosa were internalized and killed by neutrophils and macrophages more efficiently than WT and Psl⁺⁺ variants. Deposition of complement components C3, C5 and C7 was significantly higher on psl‐deficient strains compared with WT and Psl⁺⁺ bacteria. In an in vivo pulmonary competition assay, there was a 4.5‐fold fitness advantage for WT over psl‐deficient P. aeruginosa. Together, these data show that Psl inhibits efficient opsonization, resulting in reduced neutrophil ROS production, and decreased killing by phagocytes. This provides a survival advantage in vivo. Since phagocytes are critical in early recognition and control of infection, therapies aimed at Psl could improve the quality of life for patients colonized with P. aeruginosa.