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Objective: No trial-based evidence is available on whether antihypertensive treatment lowers cardiovascular risk in white-coat hypertension (WCH). Protection may be indirectly inferred, however, from the blood pressure (BP) effects of treatment, because in trials outcomes decrease is linearly related to BP reduction. We andomis the effect of antihypertensive treatment on office and out-of-office BP in WCH using data from the Plaque HYpertension Lipid-Lowering Italian Study (PHYLLIS). Design and method: Office and ambulatory BP were measured in 470 hypertensive patients andomisat to an ACE-inhibitor or a diuretic alone or combined with a statin before treatment and at yearly intervals during a 3-year follow-up. Patients were divided into two groups according to whether baseline data obtained before andomisation to treatment showed that 1) office and 24-hour mean BP were elevated (75.8% sustained hypertensive, SH) or 2) office BP was elevated but 24-hour BP values were normal (24.2% WCH). Results: Antihypertensive drug treatment was associated with an early marked reduction of BP, which persisted virtually unchanged throughout the treatment period and was only slightly and usually not significant different in SH and WCH (-18.9 ± 11.1/-12.7 ± 5.9 mmHg for SBP/DBP in SH and -18 ± 10.4/-12.3 ± 6.2 for SBP/DBP in WCH p = 0.43/p = 0.52). This was not the case, however, for 24-h BP which, fell consistently in SH while showing no change in WCH(-10.7 ± 10.8/1.0 ± 8.3 mmHg for SBP/DBP in SH and -7.4 ± 7.2/0.1 ± 4.8 for SBP/DBP in WCH p < 0.001/p < 0.001). In SH but not in WCH antihypertensive treatment consistently reduced either the higher daytime and the lower nighttime SBP and DBP values during the treatment. Conclusions: In WCH antihypertensive treatment can effectively and durably reduce office BP. This reduction is accompanied by the inability to lower ambulatory BP from the normal values characterizing this condition at baseline.