Background <p>Prolactinomas are the most common type of pituitary adenomas, typically managed with dopamine agonists. However, some cases are refractory to standard therapies, posing significant clinical challenges. This case highlights the complexities of managing an aggressive macroprolactinoma resistant to conventional treatments and explores the use of immunotherapy as a novel intervention.</p> Case presentation <p>A 54-year-old male with a history of hypertension and type 2 diabetes mellitus presented with erectile dysfunction and low libido, leading to a diagnosis of prolactinoma. Over an 18-year period, he underwent multiple interventions, including cabergoline therapy, four transsphenoidal surgeries, radiation therapy, and various pharmacotherapies. Despite these, he had refractory disease with markedly elevated prolactin levels and tumor growth. In the final stages of the disease, pembrolizumab immunotherapy was attempted. Unfortunately, the patient’s condition continued to deteriorate, ultimately leading to hospice care and death at the age of 71.</p> Conclusions <p>This case underscores the challenges associated with managing refractory prolactinomas and highlights the need for innovative therapeutic strategies, including immunotherapy. Further research is essential to establish the role of emerging treatments in improving outcomes for patients with aggressive pituitary adenomas.</p>