Primary resistance to dopamine agonists occurs in 10-15% of prolactinomas but secondary resistance following initial biochemical and anti-proliferative response is very rare and has only been hitherto described in four previous cases, two with bromocriptine and two with cabergoline. We describe a case of a 57-year-old woman who presented with a large macroprolactinoma with suprasellar extension. She was initially treated with bromocriptine therapy with a resolution of symptoms, marked reduction in prolactin concentration and complete tumour shrinkage; a response which was subsequently maintained on cabergoline. After 8 years of dopamine agonist therapy, her prolactin concentration began to rise and there was symptomatic recurrence of her tumour despite escalating doses of cabergoline up to 6 mg weekly. Non-compliance was outruled by observed inpatient drug administration. The patient underwent surgical debulking followed by radiotherapy with good response. This case adds to the previous two cases of secondary resistance to cabergoline therapy in prolactinomas a marked initial response. While the mechanism of secondary resistance remains unknown and not possible to predict, close observation of prolactinoma patients on treatment is necessary.