Context and Objective: Predicting pituitary tumor behavior remains a challenge. This multiparameter investigation aimed to identify markers for recurrence and progression in prolactin tumors. Design: From a cohort of patients treated for prolactin tumors by surgery, we retrospectively studied clinical data, tumor characteristics, clinical outcome, and the expression of nine genes by quantitative RT-PCR. Results: This study included 94 patients (62 females and 32 men), with long postoperative follow-up periods (mean, 138 ± 46 months); 54.3% of patients had a macro or giant adenoma. Tumors were classified into three pathological groups based on their radiological and histological characteristics (noninvasive, 61; invasive, 22; and aggressive-invasive, 11). Immediately after surgery, 60 patients (63.8%) went into remission (prolactin level normalization). Persistently elevated prolactin levels (36.2%) were associated with increasing age, male sex, high preoperative prolactin levels, large tumor size on univariate analysis, and invasion and pathological classification on univariate and multivariate (P = 8 × 10 -10 and 3 × 10 -8) analysis. During follow-up, 19 patients (20%) had tumors that recurred or progressed under dopamine agonist treatment. Invasion and pathological classification were associated with recurrence or progression on univariate analysis. Seven genes (ADAMTS6, CRMP1, PTTG, ASK, CCNB1, AURKB, and CENPE) were associated with tumor recurrence or progression and five of these (ADAMTS6, CRMP1, ASK, CCNB1, and CENPE) were associated with the pathological classification. Conclusion: This study identifies both the clinical and histological factors that relate to prolactin tumor recurrence or progression. Molecular markers give additional information for prognosis of such tumors. Altogether, our results could influence the management of patients with pituitary tumors. Copyright © 2010 by The Endocrine Society.