Bacteria from the complex grow in different natural and man-made environments and are feared opportunistic pathogens that cause chronic respiratory infections in cystic fibrosis patients. Previous studies showed that mucoid clinical isolates grown under stress conditions give rise to nonmucoid variants devoid of the exopolysaccharide cepacian. Here, we determined that a major cause of the nonmucoid morphotype involves nonsynonymous mutations and small indels in the gene encoding a response regulator of a two-component regulatory system. In complementation of nonmucoid variants (NMVs) with the native gene restored exopolysaccharide production. The loss of functional OmpR had positive effects on growth, adhesion to lung epithelial cells, and biofilm formation in high-osmolarity medium, as well as an increase in swimming and swarming motilities. In contrast, phenotypes such as antibiotic resistance, biofilm formation at low osmolarity, and virulence in were compromised by the absence of functional OmpR. Transcriptomic studies indicated that loss of the gene affects the expression of 701 genes, many associated with outer membrane composition, motility, stress response, iron acquisition, and the uptake of nutrients, consistent with starvation tolerance. Since the stresses here imposed on may strongly resemble the ones found in the cystic fibrosis (CF) airways and mutations in the gene from longitudinally collected CF isolates have been found, this regulator might be important for the production of NMVs in the CF environment. Within the cystic fibrosis (CF) lung, bacteria experience high-osmolarity conditions due to an ion unbalance resulting from defects in CF transmembrane conductance regulator (CFTR) protein activity in epithelial cells. Understanding how bacterial CF pathogens thrive in this environment might help the development of new therapeutic interventions to prevent chronic respiratory infections. Here, we show that the OmpR response regulator of one of the species found in CF respiratory infections, , is involved in the emergence of nonmucoid colony variants and is important for osmoadaptation by regulating several cell envelope components. Specifically, genetic, phenotypic, genomic, and transcriptomic approaches uncover OmpR as a regulator of cell wall remodeling under stress conditions, with implications in several phenotypes such as exopolysaccharide production, motility, antibiotic resistance, adhesion, and virulence.