OBJECTIVES Non-adherence to drug therapy poses a significant problem in the treatment of patients with presumed resistant hypertension (RH). It has been shown that therapeutic drug monitoring (TDM) is a useful tool for detecting non-adherence and identifying barriers to treatment adherence, leading to effective blood pressure (BP) control. However, the cost-effectiveness of TDM in the management of RH has not been investigated. METHODS A Markov model was used to evaluate life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in RH patients receiving either TDM optimized therapy or standard best medical therapy. The model ran from the age of 30 to 100 years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Cost analyses were performed from a payer’s perspective. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of €3,854 and €3,922, respectively. Given a willingness-to-pay threshold of €35,000 per QALY gained, the probability of TDM being cost-effective was ≥95% in all age groups from 30 to 90 years. Results were influenced mostly by the frequency of TDM testing, the rate of non-responders to TDM, and the magnitude of effect of TDM on BP. CONCLUSIONS Therapeutic drug monitoring presents a potentialy highly cost-effective health care intervention in patients diagnosed with RH. Importantly, this finding is valid for a wide range of patients, independent of gender and age.