The lower airways of patients with chronic respiratory diseases are often colonized by opportunistic pathogens resulting in immune activation that includes the recruitment of neutrophilic granulocytes. Despite the presence of large number of neutrophils, bacterial infections are often not cleared and prolonged colonization of the lungs is associated with increased inflammation and a more rapid decline in lung function. We examined how non-typeable Haemophilus influenzae, a bacterium that frequently colonizes the lower airways, evades neutrophil-mediated killing. Tn-seq was used on a resistant isolate to identify genes required for its survival in the presence of human neutrophils and serum, which provided a source of complement and antibodies. Results show that non-typeable Haemophilus influenzae prevents complement-dependent neutrophil-mediated killing by expression of surface galactose-containing oligosaccharide structures. These outer core structures block recognition of an inner core lipooligosaccharide epitope containing glucose attached to heptose [HepIII – Glc] by replacement with galactose attached to heptose [HepIII – Gal] or through shielding the [HepIII – Glc] by phase-variable attachment of oligosaccharide chain extensions. When the [HepIII – Glc] containing epitope is expressed and exposed, non-typeable Haemophilus influenzae is opsonized by naturally-acquired IgM generally present in human serum and subsequently phagocytosed and killed by human neutrophils. Clinical non-typeable Haemophilus influenzae isolates containing [HepIII – Gal] that are not recognized by this IgM are more likely to cause invasive infections.