Radioactive iodine (RAI)-induced thyrocyte destruction may lead to uncontrolled inflammation. This study was designed to evaluate the prophylactic and therapeutic immunomodulatory effects of omega-3 fatty acids in patients with differentiated thyroid cancer scheduled for RAI ablation. A total of 85 patients were divided into two groups based on radioiodine dosage after thyroidectomy: high-dose with 150 mCi and intermediate-dose with 100 mCi. Then patients in each group were randomly divided into three subgroups: G1 with RAI ablation only, G2 treated with omega-3 for 30 days before RAI ablation, and G3 treated with omega-3 for 30 days after RAI ablation. Serum cytokine levels were determined with the cytometric bead assay at different time points. Within-group comparisons showed transient elevation of IL-13 after pretreatment with omega-3, significant reductions in Th1+Th17/Th2+Th22 ratio after high-dose RAI ablation, and decreased Th1+Th17/Th2+Th22 and Th1+Th17/Th2+Th9+Th22 ratios after intermediate-dose RAI ablation in G2. Between-group comparisons showed that IL-10 level in G3 was significantly higher than in G1 1 week after high-dose RAI ablation, whereas Th1+Th17/Th2+Th22 and Th1+Th17/Th2+Th9+Th22 ratios were significantly lower in G3 than G2 1 month after intermediate-dose RAI ablation. However, cytokine changes 1 week and 1 month after RAI ablation when adjusted for baseline values showed no differences among groups. Despite observing within-group changes in some cytokines, we found no real changes attributable to a prophylactic or therapeutic anti-inflammatory effect of omega-3. Because of the specific effect of radioactive iodine on thyroid cells, extensive systemic inflammation may not be induced after RAI ablation.