High levels of tissue inflammation and oxidative stress are commonly associated with Haemophilus influenzae (Hi) infections of the lower respiratory tract. Here we have investigated how Hi is able to resist and thrive in the presence of reactive chlorine species such as hypochlorite, that is produced by host peroxidases during infection. Hi resistance to hypochlorite is high, with 250 mM being sublethal, compared to 75 mM reported as lethal in E. coli. We have linked this high level of HOCl resistance to a group of enzymes that are located in the Hi periplasmic space and are involved in repairing oxidative damage to sulfur compounds that results from HOCl exposure. Of these enzymes, the MsrAB peptide methionine sulfoxide reductase was required for Hi resistance to HOCl and survival during infection. This enzyme appears to have a pivotal role in maintaining integrity of the Hi cell envelope, and surprisingly, MsrAB had immunomodulatory effects on the host cells during infection. Further analysis of the cellular mechanisms of HOCl resistance identified a novel regulator, the extracytoplasmic function sigma factor RpoE2. RpoE2 controls expression of more than 20 genes, including msrAB and mtsZ, and likely has a role in mediating resistance to other types of stress. The activity of RpoE2 is controlled by a peptide-antisigma factor, HrsE, that harbours a functionally significant Zn -binding motif. While RpoE2 is the key regulator of msrAB, our data also reveal that Hi HOCl resistance mechanisms are complex and likely involved additional elements and overlapping regulatory circuits.