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It has been suggested that polyandry allows females to increase offspring genetic diversity and reduce the prevalence and susceptibility of their offspring to infectious diseases. We tested this hypothesis in wild‐derived house mice (Mus musculus) by experimentally infecting the offspring from 15 single‐ and 15 multiple‐sired litters with two different strains of a mouse pathogen (Salmonella Typhimurium) and compared their ability to control infection. We found a high variation in individual infection resistance (measured with pathogen loads) and significant differences among families, suggesting genetic effects on Salmonella resistance, but we found no difference in prevalence or infection resistance between single‐ vs. multiple‐sired litters. We found a significant sex difference in infection resistance, but surprisingly, males were more resistant to infection than females. Also, infection resistance was correlated with weight loss during infection, although only for females, indicating that susceptibility to infection had more harmful health consequences for females than for males. To our knowledge, our findings provide the first evidence for sex‐dependent resistance to Salmonella infection in house mice. Our results do not support the hypothesis that multiple‐sired litters are more likely to survive infection than single‐sired litters; however, as we explain, additional studies are required before ruling out this hypothesis.