Haemophilus influenzae is a host adapted pathogen that causes a variety of acute and chronic infections including otitis media, non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD). A novel strategy for identifying targets for antimicrobial therapy is to target metabolic enzymes and pathways to undermine the pathogen’s ability to survive in the host, and non-typeable Haemophilus influenzae (NTHi) is capable of persisting and causing infection in body niches such as the middle ear, the nasopharynx and the lung. We have investigated the metabolic changes that NTHi metabolism undergoes in adaptation to different oxygen concentrations using a standard laboratory strain (HIRD) and a COPD derived patient isolate (HI2019). While both strains have a nearly identical genetic make-up, they showed altered spectra of final products indicating subtle adaptation in pathway control: while HIRD produced mainly produced acetate, HI2019 produced mostly formate under oxygen limited conditions. This is in contradiction to metabolic models using simulation of end-products, where acetate was usually considered as the main endproduct produced. The metabolic products of the two NTHi strains are reminiscent of mixed acid fermentation, however, both strains possess a variety of respiratory pathways including several alternative terminal reductases. These putative energy generating enzymes were highly expressed under mostly anaerobic conditions, however, at least one of these enzymes, a putative DMSO reductase (DmsA), is supposed to convert a substrate that is not present in the human body. Nevertheless, a dmsA mutant strain showed defects in biofilm formation and colonization of epithelial cells. We propose that this and possible additional, related enzymes may act on sulfoxides produced from e.g. sulfur containing amino acids during interaction of NTHi with the immune system.