Dopamine agonist (DA)-resistant prolactinomas are rare but they constitute a real challenge, since there are few therapeutic alternatives left for these patients. Proof-of-concept study at a tertiary care, referral center. The studied population consisted of five patients (one female and four males, mean age at diagnosis 23.5 ± 19) with macroprolactinomas with persistent hyperprolactinemia and/or tumor mass despite high doses of cabergoline (CBG) and pituitary surgery, to whom 20 mg monthly of octreotide LAR was added for 6-13 months. Response was evaluated by measuring prolactin (PRL) levels and by magnetic resonance imaging. Immunohistochemistry (IHC) for pituitary hormones, Ki-67, and somatostatin receptor subtypes 2 and 5 was (SSTR2 and 5) was available in two of the subjects. The addition of octreotide LAR to ongoing CBG treatment had no effect on either PRL levels or tumor size in three patients. In two of the five patients, combination treatment resulted in a significant reduction in PRL concentrations (from 7643 to 200 ng/mL and from 2587 to 470 ng/mL) as well as in adenoma size (93% reduction). IHC evaluation of tumor samples from two patients (a responder and a non-responder) revealed positive immunostaining for PRL and SSTR5 but not for other pituitary hormones or for SSTR2. The addition of a somatostatin analog to ongoing CBG treatment may be effective in some patients with DA-resistant macroprolactinomas, independently of the adenoma's SSTR expression profile.