We enrolled 347 hypertensive patients, randomly allocated them to different first-line treatments, and followed-up for 24 months. Persistence on treatment was significantly higher in patients treated with ARBs (68.5%) and ACE inhibitors (64.5%) vs. CCBs (51.6%), beta-blockers (44.8%), and diuretics (34.4%). No ARB, ACE inhibitor, beta-blocker, or diuretic was associated with a greater persistence in therapy as compared with the other molecules used in each therapeutic class. The rate of persistence was significantly higher in patients treated with lercanidipine vs. other CCBs (59.3% vs. 46.6%). Systolic and diastolic BP decreased more in patients treated with ARBs (-11.2/-5.8 mmHg), ACE inhibitors (-10.5/-5.1 mmHg), and CCBs (-8.5/-4.6 mmHg) when compared to beta-blockers (-4.0/-2.3 mmHg) and diuretics (-2.3/-2.1 mmHg).