The purpose of this study was to evaluate the cost-effectiveness of comprehensive treatment strategy, including segmental adrenal venous sampling (sAVS) and radiofrequency ablation (RFA), versus medication-only strategy for primary aldosteronism. A Markov decision model was developed to compare the cost-effectiveness of a comprehensive treatment strategy and a medication-only strategy for 50-year-old men and women with stage I-III hypertension. The comprehensive treatment strategy included aldosterone/renin ratio measurement, two loading tests, computed tomography, sAVS, drugs, surgery, and RFA. We built a model with a yearly cycle over 32- and 38-year time horizons for men and women, respectively, and four health states: hypertension, heart failure, stroke, and death. The incremental cost-effectiveness ratio (ICER), expressed as Japanese yen per quality-adjusted life-years (QALYs), was estimated, and strategy preference was determined on the basis of 5 million Japanese yen per QALY societal willingness-to-pay threshold. The ICERs of the comprehensive treatment strategy over the medication-only strategy were 201,482 and 3,399 JPY per QALY for men and women, respectively. The resultant ICER was less than the 5 million JPY societal willingness-to-pay threshold. Deterministic sensitivity analysis and probabilistic sensitivity analysis revealed that the results varied with the input values, but the comprehensive strategy was likely to be more cost-effective than the medication-only strategy. This cost-effectiveness study revealed that a comprehensive treatment strategy including sAVS and RFA was favorable compared with the medication-only strategy for managing stage I-III hypertension in 50-year-old men and women, with acceptable willingness-to-pay thresholds. This cost-effectiveness study revealed that a comprehensive treatment strategy for primary aldosteronism that included segmental adrenal sampling and radiofrequency ablation was favorable compared with the medication-only strategy for managing stage I-III hypertension in 50-year-old men and women, with acceptable willingness-to-pay thresholds.