Objective(s): Cardiovascular disease (CVD) remains a leading cause of mortality in chronic kidney disease (CKD) patients. Interventions targeting traditional risk factors have largely proven ineffective in CKD patients in part because of the increased role of nontraditional risk factors such as chronic inflammation. Omega-3 fatty acids (ω3FA) are inexpensive and safe natural agents, which target inflammation and have potential cardioprotective benefits. The aim of the study was to determine the effects of ω3FA supplementation upon serum interleukin (IL)-12, IL-18, and highly sensitive C-reactive protein (hsCRP) in patients with Stage 3-4 CKD. Methods: We performed a post-hoc analysis of a randomized placebo-controlled trial in 73 nondiabetic CKD patients to determine the effects of ω3FA supplementation (4 g daily for 8 weeks) upon serum levels of IL-12, IL-18, and hsCRP. Results: There were no preintervention differences in IL-12, IL-18, or hsCRP between treatment groups. Postintervention levels of IL-12, IL-18, and hsCRP were similar between the treatment groups. However, IL-12 and IL-18 increased in both treatment groups over the intervention period, whereas hsCRP remained unchanged. The magnitude of increase in serum IL-18 (ΔIL-18) was significantly less in participants in the ω3FA treatment group compared to placebo (P =.047). Conclusion(s): This study has shown that 4 g daily ω3FA supplementation may lower serum IL-18 levels in patients with moderate CKD. Although there were no apparent effects on several other markers of inflammation, this study provides evidence for a specific effect of ω3FA on inflammatory pathways.