There is surprising heterogeneity within a natural population in the ability to transmit disease. This phenomenon of ~20% of a population being responsible for ~80% of transmission events (‘the 80/20 rule’) is understudied. In the case of infections with host-adapted pathogens, the hosts that transmit disease are often asymptomatic. Although this host-pathogen interaction has been described in humans and animals, surprisingly little is known about what distinguishes asymptomatic hosts that transmit disease from the rest of the infected population. We use a mouse model of Salmonella infection to study these phenomena. A subset of infected mice become supershedders, shedding high levels of bacteria (>108 cfu per g feces), but remain asymptomatic with a dampened immune state. We show that supershedder hosts remain asymptomatic when treated with oral antibiotics. In contrast, nonsupershedder hosts that are treated with oral antibiotics rapidly shed high levels of the pathogen but display signs of morbidity. Morbidity is linked to an increase in inflammatory myeloid cells in the spleen and increased production of acute-phase proteins and inflammatory cytokines. We describe a unique disease-associated immune tolerance to oral antibiotics in supershedders that facilitates continued transmission of the pathogen.