To compare the efficacy and safety of low-dose chlorthalidone + atenolol combination with atenolol and atenolol + amlodipine combination in stage I hypertensive patients uncontrolled on active run-in monotherapy. Newly diagnosed stage I hypertensive patients were randomized to active run-in monotherapy either with atenolol 25 mg (98/300) or chlorthalidone 6.25 mg (100/300) or amlodipine 2.5 mg (102/300). A total of 282/300 patients (atenolol 92, chlorthalidone 91, amlodipine 99) completed the active run-in phase successfully. Patients uncontrolled on active run-in monotherapy (atenolol 33, chlorthalidone 45, amlodipine 47) received the study treatment, namely atenolol 50 mg alone, chlorthalidone 6.25 mg+atenolol 25 mg and atenolol 25 mg+amlodipine 2.5 mg, respectively. Efficacy of the therapy was evaluated by BP measurement at weeks 12 and 20 post-therapy. Post-active run-in monotherapies, the study treatment groups showed a significant fall in mean SBP and DBP from baseline (p<0.05). The mean fall in SBP and DBP was comparable for study treatments (atenolol 50 mg, atenolol 25 mg+chlorthalidone 6.25 mg and atenolol 25 mg+amlodipine 2.5 mg) (p=0.337 for SBP and p=0.054 for DBP) at week 12 and (p=0.744 for SBP and p=0.855 for DBP) at week 20; also, the percentage of responders was comparable for the three study treatment groups (p=0.799) indicating that the low-dose chlorthalidone+atenolol combination is noninferior to the high-dose atenolol alone and atenolol+amlodipine combination. No serious laboratory/clinical adverse events were reported in this study. Chlorthalidone 6.25 mg in combination with atenolol 25 mg is effective and safe in stage I (JNC 7) essential hypertensive patients. This low dose of chlorthalidone could reduce dose-related concerns over metabolic adverse effects and may lead to wider usage of this proven antihypertensive agent in combination therapy.