BackgroundTranssphenoidal hypophysectomy is one of the treatment strategies in the comprehensive management of dogs with pituitary‐dependent hypercortisolism (PDH).ObjectivesTo describe the influence of pituitary size at time of pituitary gland surgery on long‐term outcome.AnimalsThree‐hundred–and‐six dogs with PDH.MethodsSurvival and disease‐free fractions were analyzed and related to pituitary size; dogs with and without recurrence were compared.ResultsFour weeks after surgery, 91% of dogs were alive and remission was confirmed in 92% of these dogs. The median survival time was 781 days, median disease‐free interval was 951 days. Over time, 27% of dogs developed recurrence of hypercortisolism after a median period of 555 days. Dogs with recurrence had significantly higher pituitary height/brain area (P/B) ratio and pre‐operative basal urinary corticoid‐to‐creatinine ratio (UCCR) than dogs without recurrence. Survival time and disease‐free interval of dogs with enlarged pituitary glands was significantly shorter than that of dogs with a non‐enlarged pituitary gland. Pituitary size at the time of surgery significantly increased over the 20‐year period. Although larger tumors have a less favorable prognosis, outcome in larger tumors improved over time.Conclusions and Clinical ImportanceTranssphenoidal hypophysectomy is an effective treatment for PDH in dogs, with an acceptable long‐term outcome. Survival time and disease‐free fractions are correlated negatively with pituitary gland size, making the P/B ratio an important pre‐operative prognosticator. However, with increasing experience, and for large tumors, pituitary gland surgery remains an option to control the pituitary mass and hypercortisolism.