Secondary resistance to dopamine agonists is a rare phenomenon in patients with a prolactinoma. We describe a 55-year-old male with a macroprolactinoma initially responding favorably to bromocriptine treatment with normalization of prolactin levels and tumor shrinkage. Two years later, he developed resistance to bromocriptine treatment and subsequently to cabergoline. The aggressive course of the disease necessitated three surgical interventions. Staining of the pituitary tissue revealed a very high MIB/Ki-67 labeling index that increased further in specimens derived from repeated surgery. This case demonstrates that high and increasing levels of the MIB/Ki-67 labeling index may indicate an aggressive course associated with secondary dopamine resistance.