Background and aim <p>Cushing’s disease (CD) is associated with phenotypic traits and comorbidities that may persist after the normalization of cortisol levels. Medical therapy is usually given in recurrent or persistent CD after transsphenoidal surgery. We aimed to investigate the impact of long-term normalization of daily cortisol secretion on clinical picture and cardiometabolic comorbidities, comparing surgical remission to medical treatment.</p> Methods <p>Monocentric retrospective study, two- and five-years observation. Sixty CD patients, with sustained normal 24-h urinary free cortisol (UFC) levels, divided group 1 (surgical remission, <i>n</i> = 36) and group 2 (medical remission, <i>n</i> = 24).</p> Results <p>Patients were different after achieving eucortisolism with surgery or medical treatment. Phenotypic traits: round face, dorsocervical fat pad, and bruisability persisted more prominently in the group 2, however abdominal obesity and muscle weakness persisted in both groups, especially in those patients with increased late-night salivary cortisol (LNSC). Hypertension: greater improvement was observed in group 1 (-31% vs. -5%, <i>p</i> = 0.04). Diabetes: less prevalent in group 1 after 2 years (2/36 vs. 9/24, <i>p</i> = 0.002), with a corresponding reduction in glucose-lowering treatments and persistence of impaired LNSC in diabetic patients (<i>p</i> &lt; 0.001). Dyslipidemia: remained widespread in both groups, with minimal improvement over time (-22% in surgical and − 6% in medical cohort).</p> Conclusions <p>Surgical remission leads to faster and sustained improvements in clinical phenotype. However, obesity, arterial hypertension, and dyslipidemia do not completely revert in five years, especially during medical treatment. Most comorbidities persist despite UFC normalization, due to impaired LNSC: the recovery of cortisol rhythms confirms the remission of hypercortisolism.</p>