In most cases, papillary thyroid cancer (PTC) is highly curable and associated with an excellent prognosis. Yet, there are several clinicopathological features that lead to a poor prognosis, underscoring the need for a better genomic strategy to refine prognostication and patient management. We hypothesized that PPARγ targets could be potential markers for better diagnosis and prognosis due to the variants found in PPARG in three pairs of monozygotic twins with PTC. Here, we developed a 10-gene personalized prognostic index, designated PPARGi, based on gene expression of 10 PPARγ targets. Through scRNA-seq data analysis of PTC tissues derived from patients, we found that PPARGi genes were predominantly expressed in macrophages and epithelial cells. Machine learning algorithms showed a near-perfect performance of PPARGi in deciding the presence of the disease and in selecting a small subset of patients with poor disease-specific survival in TCGA-THCA and newly developed merged microarray data (MMD) consisting exclusively of thyroid cancers and normal tissues.