Background: Chinese Hypertension Intervention Efficacy (CHIEF) study is a large-scale randomised clinical trial across China, which compares the efficacy of two combination regimens in reducing cardiovascular events associated with hypertension. Methods: We reported the 48-week efficacy and tolerability of the two antihypertensive regimens in participants from Shandong Province, China. Eligible patients aged 5079 years were randomised to receive amlodipine plus amiloride/hydrochlorothiazide (Group A) or amlodipine plus telmisartan (Group B). The doses of both regimens were titrated and other antihypertensive agents were added subsequently to achieve a blood pressure (BP) goal (<140/90 mmHg for general population, <130/80 mmHg for diabetics and <150/90 mmHg for elderly). Efficacy variables included the changes of BP, control rates (the proportion of patients achieving a BP goal), and response rates (the proportion of patients achieving a BP goal or a reduction of BP =20/10 mmHg). Safety was assessed by monitoring the incidence of adverse events (AEs). Results: Of the 349 patients enrolled, 314 were randomised and 291 completed the study (141 in Group A and 150 in Group B). At week 48, the BP was reduced by 28.77/15.55 mmHg in Group A and by 31.38/16.07 mmHg in Group B (p > 0.05 for comparisons between Group A and Group B). The control rates (71.79% vs. 77.22%; p = 0.270) and response rates (79.49% vs. 84.81%; p = 0.218) were also similar. For both regimens, the control rates in diabetic patients were relatively lower (31.91% and 32.50%), while those in elderly patients were pretty higher (90.74% and 97.62%). AEs were mild to moderate in severity (17.95% vs. 12.66%, p = 0.193). Conclusion: Both combination regimens, amlodipine plus amiloride/hydrochlorothiazide and amlodipine plus telmisartan, were effective and safe for the high-risk hypertensive patients.