Backgrounds: Prolactin secreting pituitary tumors (PRL-omas) represent a unique challenge for endocrinologists and neurosurgeons. Considering recent innovations in surgical, we aimed to investigate the best management for PRL-omas. Methods: A retrospective, cross-sectional and monocentric study was designed. Consecutive patients affected for PRL-omas were enrolled if treated with first line treatment with dopamine-agonist (DA) or trans-sphenoidal surgery (TSS). Patients carried giant PRL-omas and those with a follow-up < 12 months were excluded. Results: 259 patients were enrolled. The first treatment was DA for 140 patients and TSS for 119 cases. 146 of 249 patients (58.6%) needed a second therapy. Mean follow up was 102.2 months (12-438 months). Surgery highly impacted on the cure rate, in particular in females (p=0.0021) and in micro- PRL-omas (p=0.0020). Considering multivariate analysis, female gender and surgical treatment in the course of clinical history were the only independent positive predictors of cure at the end of 5 years follow-up (p=0.0016, p=0.0005). The evaluation of serum prolactin (24 hours after TSS) revealed that 86.4% of patients with post-operative PRL≤10 ng/ml resulted cured at the end of follow-up (p< 0.0001). Conclusion: According to our experience, surgery allows a higher cure rate of PRL-omas, in particular in females with micro-PRL-omas, with a good safety profile. TSS for PRL-oma should be considered as first line therapy, in the management of patients, during the multidisciplinary evaluation, in center of reference for pituitary diseases, in order guarantee a valid surgical outcome and a safety profile.