The mycotoxin deoxynivalenol (DON) has been shown to regularly occur at relevant concentrations in feed designed for aquaculture use, but little is known about the consequences of its presence on the organisms that consume the DON-contaminated feed. Previous studies indicated a down-regulation of pro-inflammatory responses in carp (Cyprinus carpio L.) after 4 weeks of feeding DON. The present study examined the time course of innate immune responses of carp to orally administered DON. Changes in mRNA levels of immune genes in different organs (head kidney, trunk kidney, spleen, liver, and intestine) were observed indicating immune-modulating properties of DON. The immune-modulatory effects during the acute phase of DON exposure were characterized by the activation of both pro- and anti-inflammatory cytokines and enzymes in carp. The subchronic responses to DON were characterized by activation of arginases culminating in increased arginase activity in head kidney leukocytes after 26 days of DON treatment. These results suggest profound effects of this mycotoxin on fish in aquaculture.