The objective of this 8-week open-label study was to compare the tolerability of lercanidipine, a dihydropyridine calcium-channel antagonist (CA), with that of other CAs in the treatment of hypertension. Subjects already taking amlodipine, felodipine, nifedipine gastrointestinal therapeutic system (GITS), or nitrendipine and experiencing CA-specific adverse effects (AEs) were switched to lercanidipine for 4 weeks and then rechallenged with their initial treatment for 4 weeks. Results showed that at comparable levels of BP, lercanidipine was associated with a significantly lower incidence of ankle edema, flushing, rash, headache and dizziness compared with other CAs (p < 0.001). After 4 weeks of lercanidipine, mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) was 142.1/86.7 mmHg. After rechallenge with other CAs for 4 weeks, mean SBP/DBP was 141.1/86.7 mmHg. In this open-label study, lercanidipine compared with other CA seems to provide a significant improvement in tolerability with comparable antihypertensive effect.