The clinical form of natural zearalenone intoxication was observed in sheep that were kept indoors and fed a constant diet of feed concentrates containing high concentrations of zearalenone and its metabolite α-zearalenol. The clinical form of the disease was not noted in the control group, consisting of sheep that were kept on a pasture from spring to late autumn; only in the winter they were fed wheat pellets, in which the zearalenone concentration was determined to be the lowest among all used feed concentrates. During the course of natural zearalenone intoxication, metabolism of arachidonic acid increased, mainly due to enzymes of the cyclooxygenase group, which are responsible for the generation of prostaglandin F2α and thromboxane B2, and an increase in their concentration. Increased production of F2α and B2 was closely correlated with the serum level of SAA, an indicator of the intensity of the inflammatory reaction. This indicates that both compounds participated in the development of inflammatory reactions in the terminal end of the digestive tract that accompanied zearalenone intoxication in sheep. The imbalances noted between the eicosanoid classes investigated in this study were fundamentally responsible for the development of clinical symptoms in sick sheep that showed symptoms of partial or total prolapse of the anus and rectum and prolapse of the large intestine, which were the direct cause of the animals death.