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Cell surface mucin glycoproteins are highly expressed by all mucosal tissues, yet their physiological role is currently unknown. We hypothesized that cell surface mucins protect mucosal cells from infection. A rapid progressive increase in gastrointestinal expression of mucin 1 (Muc1) cell surface mucin followed infection of mice with the bacterial pathogen Campylobacter jejuni. In the first week following oral infection, C. jejuni was detected in the systemic organs of the vast majority of Muc1–/–mice but never in Muc1+/+ mice. Although C. jejuni entered gastrointestinal epithelial cells of both Muc1–/–and Muc1+/+ mice, small intestinal damage as manifested by increased apoptosis and enucleated and shed villous epithelium was more common in Muc1–/–mice. Using radiation chimeras, we determined that prevention of systemic infection in wild-type mice was due exclusively to epithelial Muc1 rather than Muc1 on …