Disease resistant hosts are central in the spread, persistence, adaptation and diversification of infectious pathogens. In theory, resistant hosts must compromise on reproduction and invest more energy in self maintenance and immune defence. Here we investigated these hypotheses on the emergence of West Nile Virus (WNV) from 1999 to 2012 in the United States, when the virus caused mass mortality in some bird species. Our study comprehends two steps: First, we used regression tree meta-analysis on 233 reports of dead birds from 90 species, to test correlations between WNV-linked mortality and the birds’ life history and ecological traits. Second, we tested links between diversification of WNV and the reproductive investment and self-maintenance of its avian hosts, by analysing the phylogeography of 520 genome sequences of WNV from 1999 to 2012. Statistical analyses revealed less WNV-linked mortality in both, species that incubate their eggs for few days (>17) and large species (>235g). The evolutionary trajectory of the virus suggests that there was no special viral strain infecting the most and the less vulnerable species. However, by 2012 the WNV strains found in large birds like American crows (Corvus brachyrhynchos) diversified and evolved separately from the rest. Together, our findings support that hosts’ reproductive investment impairs disease resistance, and hosts investing in self-maintenance may lead WNV diversification.