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Background Observational studies suggest there are differences in adherence to antihypertensive medications in different classes. Our objective was to quantify the association between antihypertensive drug class and adherence in clinical settings. Methods and Results Studies were identified through a systematic search of English-language articles published from inception of computerized databases till February 1, 2009. Studies were included if they measured adherence to antihypertensives using medication refill data and contained sufficient data to calculate a measure of relative risk of adherence and its variance. An inverse-variance weighted random-effects model was used to pool results. Hazard ratios (HR) and odds ratios (OR) were pooled separately, and HRs were selected as the primary outcome. Seventeen studies met inclusion criteria. The pooled mean adherence by drug class ranged from 28% for beta-blockers to 65% for angiotensin II-receptor blockers (ARBs).There was better adherence to ARBs compared to angiotensin-converting enzyme inhibitors (ACEIs) (HR 1.33, 95%CI 1.13–1.57), calcium channel blockers (HR 1.57, 95% CI 1.38–1.79), diuretics (HR 1.95, 95%CI 1.73–2.20), and beta-blockers (HR 2.09, 95%CI 1.14–3.85). Conversely, there was lower adherence to diuretics compared to the other drug classes. The same pattern was present when pooling studies that used ORs. When accounting for publication bias, there were no longer significant differences in adherence between ARBs and ACEIs or between diuretics and beta-blockers. Conclusion In clinical settings, there are important differences in adherence to antihypertensives in separate classes with lowest adherence to diuretics and beta-blockers and highest to ARBs and ACEIs. Yet, adherence was suboptimal regardless of drug class.