Purpose <p>Liver cancer prognosis is associated with M0 macrophages and lipid metabolism reprogramming; however, the prognostic role of M0 macrophage-related lipid metabolism genes in hepatocellular carcinoma (HCC) remains unclear.</p> Methods <p>We identified 153 lipid metabolism genes associated with M0 macrophage infiltration in HCC from The Cancer Genome Atlas (TCGA) and the Molecular Signatures Database (MSigDB). Prognostic genes were selected, and a model was constructed using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. The model was validated using the International Cancer Genome Consortium (ICGC) database. We assessed the expression levels of prognostic genes by quantitative real-time polymerase chain reaction (qRT‒PCR).</p> Results <p>A prognostic model was developed based on five characteristic genes. Receiver operating characteristic curve analysis demonstrated that the model had good accuracy, with area under the curve values of 0.796, 0.732, and 0.728 for predicting survival at 1, 3, and 5&#xa0;years, respectively. The high-risk group exhibited increased sensitivity to common chemotherapy drugs, including sorafenib, dasatinib, and 5-fluorouracil, compared with the low-risk group (P &lt; 0.05). Additionally, the high-risk group had significantly more infiltrating M0 macrophages, resting dendritic cells, follicular helper T cells, and regulatory T cells than did the low-risk group (P &lt; 0.05). The qRT‒PCR results confirmed the upregulation of these five characteristic genes in HCC tissues.</p> Conclusions <p>M0 macrophage-associated lipid metabolism genes may serve as biomarkers for the prognosis of patients with HCC and as targets for immunotherapy.</p>