We have previously demonstrated interferon gamma (IFN-γ) in intestinal mucosa after experimental human Cryptosporidium parvum infection, but expression was limited to sensitized volunteers. To characterize IFN-γ-independent mechanisms in control of infection, jejunal biopsies from immunocompetent volunteers experimentally challenged with C. parvum were examined by in situ hybridization for interleukin (IL-)15 and IL-4 mRNA with confirmation by immunohistochemistry. Cytokine expression was correlated with prechallenge anti-C, parvum IgG, symptoms, oocyst shedding, and prior IFN-γ expression data. IL-15 expression was noted only in those without prior sensitization, who did not express IFN-γ. By contrast, expression of IL-4 was associated with prior sensitization. IL-15 was only detected in those with symptoms (6/14 symptomatic vs 0/3 asymptomatic, P>0.05). Among 14 volunteers who did not express IFN-γ, oocyst shedding was lower in those expressing IL-15. Overall, 14/15 volunteers who did not shed oocysts expressed either IFN-γ or IL-15. There was no correlation between expression of IL-4 and symptoms or oocyst shedding. In conclusion, IL-15 expression was associated with control of oocyst shedding in those not expressing IFN-γ. These data suggest that IL-15 is involved in IFN-γ independent mechanisms of control of human cryptosporidiosis, perhaps via activation of the innate immune response.