Successful control of blood pressure relies on identification of secondary causes and contributing factors of hypertension. As antihypertensive medication can interfere with diagnostic investigations, temporary discontinuation of medication is advised. However, there are concerns about the safety of temporary discontinuation of antihypertensive medication in patients with difficult-to-control hypertension. We assessed the occurrence of adverse cardiovascular and cerebrovascular events potentially attributable to temporary discontinuation of antihypertensive medication between February 2010 and March 2016 (n=604) in our Analysis of Complicated Hypertension screening program. A reference group (n=604) was extracted from the SMART study (Second Manifestations of Arterial Disease) cohort (comprising a similar cohort at our hospital in whom medication was not stopped) and individually matched for blood pressure, age, sex, and history of cardiovascular disease. Discontinuation of medication was well tolerated; 62% reported no complaints, 24% had mild discomfort that could be left untreated, and 14% experienced complaints that required prescription of antihypertensive escape medication. Three major adverse events were observed in the Analysis of Complicated Hypertension group between discontinuation of medication and 30 days after restart of medication (event rate=31.2 events per 1000 patient-year). In the reference cohort, 5 cardiovascular events were observed during a similar follow-up period (event rate=51.2 events per 1000 patient-year). In conclusion, discontinuation of antihypertensive medication for the diagnostic evaluation of hypertension does not increase the acute risk of cardiovascular events when performed in a well-controlled setting in specialized hospitals with appropriate protocols for monitoring safety.