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In <i>Pseudomonas aeruginosa,</i> SadB acts as a post-translational adaptor protein that binds to the transcriptional regulator AmrZ. Deletion of <i>sadB</i> results in a biofilm-defective, hyperswarming phenotype. To investigate whether SadB contributes to virulence, we employed <i>in vivo</i> bioluminescence imaging and histopathology to visualize the development of infection in a mouse soft tissue model. Compared with the parent PAO1 strain, the <i>sadB</i> mutant was highly attenuated and rapidly cleared from the infection site, whereas genetic complementation conferring constitutive expression of <i>sadB</i> resulted in a much more persistent phenotype. Transcriptome analysis was undertaken to gain insights into the global impact of SadB, revealing that it modulates expression of diverse genes involved in biofilm development, quorum sensing (QS), secondary metabolite production, iron acquisition, virulence, protein secretion, and anaerobiosis. In the <i>sadB</i> mutant<i>,</i> we observed log-phase induction of the <i>rhl</i> and <i>pqs</i> QS systems, increased production of siderophores and pyocyanin, differential regulation of genes involved in c-di-GMP signaling, and a growth defect under microaerophilic conditions. The overproduction of rhamnolipids is consistent with the hyperswarming, biofilm-defective phenotype of the <i>sadB</i> mutant since rhamnolipids act as anti-adhesive surface lubricants. Deletion of <i>rhlA</i> in the <i>sadB</i> mutant resulted in the restoration of biofilm formation, offering mechanistic insight into the biofilm-defective phenotype of the <i>sadB</i> mutant. SadB clearly plays a global role in the adaptive behavior and virulence of <i>P. aeruginosa</i>.IMPORTANCEBiofilms are characterized by their intrinsic tolerance to antibiotics, host immune defenses, and ability to cause persistent infections. In <i>Pseudomonas aeruginosa,</i> mutation of the surface attachment defect gene<i>, sadB,</i> results in cells that are biofilm-defective, hyperswarmers. Here, we sought to determine whether SadB regulates virulence and influences the development of infection. In a mouse skin infection model, a <i>P. aeruginosa sadB</i> deletion mutant was highly attenuated. We also demonstrate that SadB regulates many different genes involved in virulence, quorum sensing, iron acquisition, protein secretion, and anaerobiosis as well as biofilm formation, highlighting a broader role in pathogenesis than previously recognized. Consequently, SadB has potential as a novel protein target for antibacterial drug discovery.