No head-to-head comparisons are available to analyze the efficacy of octreotide (LAR) and lanreotide (LAN) as first-line treatment of acromegaly.We compared the efficacy of these two drugs in 54 newly diagnosed patients (21 women, 33 men), 27 treated with LAR (10-30 mg every 28 days) and 27 with LAN (60-90 mg/28 days), for 12 months. Each LAR-treated patient was matched with one LAN-treated patient as for GH levels, sex, and age (+/-5 yr). Outcome measures were GH and IGF-I levels and tumor shrinkage and secondarily classical cardiovascular risk factors (total/HDL-cholesterol ratio, glucose tolerance), blood pressure and drug tolerability. In LAR- and in LAN-treated patients, respectively: GH and IGF-I were controlled in 21 (77.7%) and in 16 patients (59.3%; p=0.26); tumor shrinkage was absent (<25%) in 4 and 5 patients (p=1), mild (25.1-50%) in 9 and 12 (p=0.57), moderate (50.1-75%) in 10 and 6 (p=0.37) and notable (>75%) in 4 and 4 patients (p=1). The total/HDL-cholesterol ratio and insulin levels significantly decreased while glucose levels significantly increased in both groups. None of the patients with normal glucose tolerance at diagnosis developed diabetes mellitus. Side effects were mostly at the gastrointestinal level and were similar with both drugs. In conclusion, newly diagnosed patients with acromegaly treated with LAR and LAN have no significantly different prevalence of disease control, tumor shrinkage, improvement of cardiovascular risk markers and side effects. Therefore, both drugs can be safely employed as first-line therapy of acromegaly.