Employing a novel, comprehensive precision medicine clinical tool (PMCT) that is an LC/MS/MS-based platform (PrecisionCMQ™), we analyzed the serum of patients with hypertension (HTN) seeking emergency care (n=295) for the presence and quantity of 42 antihypertensive and cardiovascular medications. Patient-reported adherence was assessed by a validated 12-item survey; in exploratory analyses, a single item was used to classify patients as adherent/non-adherent. Adherence assessed by PMCT correlated with patient-reported adherence measured by the single-item survey. Among patients prescribed ≥ 3 antihypertensives, PMCT-based adherence was 77% in patients (n=65) who indicated they never miss a dose, versus 66% in patients (n=71) who reported missed doses (p=0.02, Kruskal-Wallis test; median prescribed medications = 3.6). Among patients with ≥ 3 prescribed antihypertensives, we found adherent patients had lower SBP (12.7 mm Hg lower, 95% CI 5.7-19.6; p<0.01) and DBP (7.5 mm Hg lower, 95% CI 3.1-11.9; p<0.01) after adjusting for age, sex, BMI, education, insurance status, administration of antihypertensives in ED and patient-reported adherence. No significant difference in BP was observed in patients prescribed 1 or 2 antihypertensives (data not shown). By comparing PMCT-based adherence to prescribed antihypertensives listed in the EHR, 11% of the detected medications (59/553) were not recorded in the patient’s EHR. Additionally, to assess whether patients with higher serum medication concentrations had lower BP, we compared SBP and DBP to medication concentrations normalized to published reference ranges. After accounting for the above covariates and the number of detected medications, we observed a relationship between medication concentration and BP across patients. Adherence assessed by PMCT provided information beyond that available from patient-report alone. These results support the utility of clinical tool-based medication monitoring for assessing adherence and improving BP control in HTN patients.