Outbreaks of infectious diseases repeatedly affected medieval Europe, leaving behind a large number of dead often inhumed in mass graves. Human remains interred in two burial pits from 14^th century CE Germany exhibited molecular evidence of <i>Salmonella enterica</i> Paratyphi C (<i>S.</i> Paratyphi C) infection. The pathogen is responsible for paratyphoid fever, which was likely the cause of death for the buried individuals. This finding presented the unique opportunity to conduct a paratyphoid fever association study in a European population. We focused on HLA-DRB1*03:01 that is a known risk allele for enteric fever in present-day South Asians. We generated HLA profiles for 29 medieval <i>S.</i> Paratyphi C cases and 24 contemporaneous controls and compared these to a modern German population. The frequency of the risk allele was higher in the medieval cases (29.6%) compared to the contemporaneous controls (13%; <i>p = 0.189</i>), albeit not significantly so, possibly because of small sample sizes. Indeed, in comparison with the modern controls (<i>n = 39,689</i>; 10.2%; <i>p = 0.005</i>) the frequency difference became statistically significant. This comparison also suggested a slight decrease in the allele's prevalence between the medieval and modern controls. Up to now, this is the first study on the genetic predisposition to <i>Salmonella</i> infection in Europeans and the only association analysis on paratyphoid fever C. Functional investigation using computational binding prediction between HLA variants and <i>S.</i> Paratyphi and <i>S.</i> Typhi peptides supported a reduced recognition capacity of bacterial proteins by DRB1*03:01 relative to other common DRB1 variants. This pattern could potentially explain the disease association. Our results suggest a slightly reduced predisposition to paratyphoid fever in modern Europeans. The causative allele, however, is still common today, which can be explained by a trade-off, as DRB1*03:01 is protective against infectious respiratory diseases such as severe respiratory syndrome (SARS). It is thus possible that the allele also provided resistance to corona-like viruses in the past.