Respiratory tract infections with Haemophilus influenzae (Hi) are characterized by high rates of recurrence and persistence, with tissue cells implicated as a likely long-term reservoir for Hi. Here we have investigated the interplay between Hi nutritional adaptations to the respiratory tract and longterm survival during infection. Our data reveal that despite the well-known genetic diversity of Hi strains, there is a common, highly specialized profile of preferred C-, N- and P-sources that includes host metabolic endproducts, such as lactate, and a variety of nucleotides and nucleosides as C-, N- and P- sources. Additionally, the spectrum of metabolic endproducts produced by Hi includes acetate and succinate, both known immunometabolites, which suggests interesting possibilities of metabolic interactions between Hi and the host cells as drivers of Hi persistence. Using pseudo-stratified epithelia derived from primary human cells as the infection model, we were able to show that a functional de-novo purine biosynthesis pathway and lactate utilization, but also the ability to produce acetate were required for longterm Hi persistence and efficient access to the intracellular niche. Additionally, a reduction in IL-8 and Il-6 responses to infection with live NTHi was observed in the presence of acetate or succinate. We propose that in contact with the human host, Hi relies on the human metabolic endproduct, L-lactate, that is converted to pyruvate on uptake, as its main carbon source, and uses ATP production from acetate formation as a main source of cellular energy, similar to what has been proposed for Shigella flexneri.