Purpose <p>This study aimed to evaluate the predictive role of peripheral blood lymphocyte subsets in therapeutic efficacy for papillary thyroid cancer (PTC) patients undergoing radioactive iodine (RAI) therapy.</p> Methods <p>A retrospective analysis was conducted on 405 PTC patients received RAI therapy. Peripheral blood lymphocyte subsets (CD3⁺, CD4⁺, CD8⁺ T cells, B cells, and NK cells) were measured using flow cytometry. Clinical outcomes were categorized as excellent/indeterminate response (ER/IDR) or biochemical/structural incomplete response (BIR/SIR) based on the 2015 ATA guidelines. Statistical analyses included ROC curves, Mann-Whitney U-tests, and multivariate regression.</p> Results <p><?tk 1?>Lymphocyte profiles varied with clinical features: older age (≥ 55 years) correlated with reduced CD8⁺ T cells (<i>P</i> &lt; 0.001), while BRAF^V600E-positive patients showed lower CD4⁺ and CD3⁺ T cells (<i>P</i> = 0.02). Lymph node metastasis (N1a/b) was associated with suppressed NK cell activity (<i>P</i> = 0.02) but elevated T-cell percentages (<i>P</i> = 0.01). B-cell counts and CD4/CD8 ratios were significant predictors of RAI response. Patients with BIR/SIR exhibited higher B-cell counts (250.0 vs. 219.0 cells/µL, <i>P</i> = 0.001) and CD4/CD8 ratios (1.6 vs.1.4, <i>P</i> = 0.02) compared to patients with ER/IDR. ROC analysis demonstrated moderate predictive accuracy for B cells (AUC = 0.601, <i>P</i> = 0.001) and CD4/CD8 ratios (AUC = 0.567, <i>P</i> = 0.027).</p> Conclusion <p>Peripheral blood lymphocyte subsets, particularly B-cell levels and CD4/CD8 ratios, may serve as biomarkers for predicting therapeutic efficacy in PTC. These findings highlight the clinical relevance of integrating immune status assessment into therapeutic decision-making, offering potential for personalized treatment strategies.</p>