Expulsion of the gastro‐intestinal nematode Trichinella spiralis is associated with a pronounced mastocytosis mediated by a T helper (Th) 2 type response involving interleukin (IL)‐4 and IL‐13. Here we demonstrate that IL‐10 is a key regulator of protective immune responses against T. spiralis in vivo. IL‐10 knockout mice or normal mice treated with a neutralizing anti‐IL‐10 receptor antibody are highly susceptible to a primary T. spiralis infection and show significantly delayed adult worm expulsion. Depletion of IL‐10 resulted in elevated Th1 and Th2 cytokine responses but significantly reduced numbers of mucosal mast cells in the jejunum. Interestingly, the increase in IFN‐γ detected in the absence of IL‐10 resulted in increased immunity to larval stages. Hence, IL‐10 has a negative effect on immunity to the tissue dwelling larval stages of T. spiralis but plays a significant biological role as an in vivo regulator of intestinal mast cell responses and is crucially involved in protection against adult stages of intestinal parasites in vivo.