Background: We previously established that male Swiss mice (Mus musculus) receiving a high-fat diet (HFD) during 8 weeks exhibit similar caloric ingestion and body weight (grams) compared with mice fed a high-carbohydrate diet (HCD). HFD mice exhibit a lower inflammatory state than an HCD in the liver, skeletal muscle, and brain. In addition, we demonstrated that HFD and HCD modulated fatty acids (FA) composition in these tissues. In this study, our objective was to compare HFD mice and HCD mice in terms of systemic inflammation. Methods: Saturated FA (SFA), monounsaturated FA, omega-6 polyunsaturated FA (n-6 PUFA), and n-3 PUFA were evaluated at the time points 0, 1, 7, 14, 28, and 56 days after starting the administration of the diets. We investigated n-6 PUFA:n-3 PUFA, SFA:n-3 PUFA, palmitic acid:α-linolenic acid (ALA), and myristic acid:docosahexaenoic acid (DHA) ratios as potential serum biomarkers of systemic inflammation. We also measured the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible protein 10 (IP-10), interferon gamma (IFN-γ), interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, macrophage inflammatory protein-1α (MIP-1-α), monocyte chemotactic protein 1 (MCP-1), monokine induced by IFN-γ (MIG), and tumor necrosis factor α (TNF-α). Results: The HFD group had lower (P < 0.05) n-6 PUFA:n-3 PUFA, palmitic acid:ALA, myristic acid:DHA ratios, and lower plasma levels of proinflammatory cytokines (IFN-γ, MIG, GM-CSF, and IL-6). Conclusion: The HFD mice showed lower systemic inflammation compared with a caloric ingestion-body weight-matched control HCD mice.