BACKGROUND Arachidonic acid (AA) is considered to link nutrient metabolism, to inflammation and immunity, suggesting it may have a role in autoimmune diseases. Our previous study suggests that DPP-4 inhibitors (DPP-4i) might regulate AA - relative signaling in type 1 diabetes. OBJECTIVE To examine the effect of AA on autoimmune diabetes and its cross-talk with DPP-4i in The Non-Obese Diabetic (NOD) mice. METHODS The NOD mice were divided randomly and equally into three groups: AA group, AA plus DPP-4i group and control group. The incidence of diabetes, blood glucose, insulitis and cytokine profiles were monitored. At the end of the experiment, pancreatic tissues were stained by H&E. Serum cytokine profiles were examined using a Mesco Scale Discovery multiplexed-assay kit. RESULTS Even though AA or AA plus DPP-4i treatment has no effect on incidence of diabetes and weight, AA treatment reduces blood glucose, preserves islet morphology and alleviates inflammatory cell infiltration into pancreatic islets in NOD mice, accompanying with increased serum levels of IL-10, IL-1 β, IL-6, IL-5, KC/GRO and TNF-α and decreased serum levels of IL-2. CONCLUSIONS We observed that AA treatment alleviates autoimmune diabetes in NOD mice by reducing hyperglycemia, alleviating insulitis and improving cytokine profiles. DPP-4i might alleviate the effect of AA by cross-talk. We provide evidence of AA treatment to alleviate type 1 diabetes in NOD mice, which may provide a novel therapeutic option for type 1 diabetes.