Ileal lesions of 36.4% of patients with Crohn's disease (CD), an inflammatory bowel disease in humans, are colonized by pathogenic adherent‐invasive Escherichia coli (AIEC), and high levels of antibodies directed against E. coli OmpC are present in 37–55% of CD patients. We therefore investigated the expression of OmpC and its role in the interaction of CD‐associated adherent‐invasive E. coli strain LF82 with intestinal epithelial cells. High osmolarity induced a significant increase in the ability of LF82 bacteria to interact with Intestine‐407 cells, which correlates with increased OmpC expression. Deletion of ompC gene markedly decreased the adhesion and invasion levels of the corresponding mutant. A LF82‐ΔompR mutant impaired in OmpC and OmpF expression, showed decreased adhesion and invasion, and unlike a K‐12‐negative OmpR mutant did not express flagella and type 1 pili. Interestingly, the wild‐type phenotype was restored when OmpC or OmpF expression was induced in the LF82‐ΔompR mutant. Overexpression of RpoE in the LF82‐ΔompR isogenic mutant restored a full wild‐type phenotype without restoring OmpC expression. Increased expression of RpoE was observed in wild‐type strain LF82 at high osmolarity. Hence, the role of OmpC in the AIEC LF82 adhesion and invasion is indirect and involves the σ^E regulatory pathway.