Abstract: Refractory hypertension (RfH) is defined as a lack of blood pressure control despite the administration of at least 5 anti-hypertensive drugs. The factors associated with its natural history are unknown. This study aimed to evaluate both the incidence of RfH in an cohort of patients with resistant hypertension (RH) and the factors involved in that progression. This was an observational prospective multicenter study (24 centers) with 172 patients with confirmed RH (24-h ABPM) who underwent a further 24 h ABPM study at the end of the follow-up. Prospective information was obtained from all patients in their corresponding Hypertension Units via a standard clinical protocol, and they all underwent a sleep study. Thirty patients were diagnosed with RfH (17.4%) after a mean follow-up of 57 months, despite the prescription of a greater number of long-acting thiazide-like diuretics and mineralocorticoid receptor antagonists. The factors associated with progression to RfH were: a longer period since the diagnosis of RH (OR: 1.06, 95% CI: 1.01-1.1, p = 0.007); the HbA1c concentration (OR: 1.42, 95% CI: 1.42-1.8; p = 0.005); the initial heart rate (OR: 1.05, 95% CI: 1.01-1.09, p = 0.004); and poor adherence to continuous positive airway pressure (CPAP) in cases of obstructive sleep apnea (OR: 3.36, 95% CI: 1.47-7.7, p = 0.004). In conclusion, a considerable percentage of patients evolved from the RH to the RfH phenotype despite changes in their treatment. Some easily measurable variables, such as heart rate, the time since the diagnosis, the HbA1c level, and the presence of untreated obstructive sleep apnea (or poor adherence to CPAP) have been demonstrated to be prognostic factors in the progression to RfH.