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BACKGROUND: Blood pressure (BP) variability (BPV) is associated with cardiovascular risk beyond mean BP. Whether first-line antihypertensive regimens differentially affect BPV and cardiovascular outcomes remains uncertain. METHODS: We conducted a target trial emulation using pooled individual participant data from 2 randomized trials: ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) and SPRINT (Systolic Blood Pressure Intervention Trial). Propensity score matching was used for pairwise comparisons of RAS (renin-angiotensin system) inhibitors, calcium channel blockers (CCBs), and diuretics, as monotherapy or in combination. Follow-up was initiated at a predefined baseline medication assessment. The primary outcome was visit-to-visit systolic BPV, assessed using variation independent of the mean. Secondary outcomes included major adverse cardiovascular events and its individual components. RESULTS: The final cohort included 5779 participants (median of 12 BP measurements and median follow-up of 3.5 years), among whom 2754 were included in the matched analysis. CCB-based regimens were consistently associated with significantly lower systolic BPV compared with both RAS inhibitor-based and diuretic-based regimens. This association was consistent across monotherapy (CCB versus RAS: β=-1.341 [95% CI, -1.930 to -0.752]; P<0.001) and combination therapies (CCB+diuretic versus RAS+diuretic: β=-1.299 [95% CI, -1.852 to -0.747]; P<0.001). In contrast, RAS inhibitor-based and diuretic-based regimens demonstrated comparable BPV profiles. A total of 215 (3.7%) major adverse cardiovascular events were observed in the overall cohort. No significant differences in major adverse cardiovascular event or individual components were observed across comparisons. CONCLUSIONS: Among high-risk hypertensive patients receiving target-driven BP management, CCB-based regimens were associated with lower visit-to-visit systolic BPV compared with RAS inhibitor-based and diuretic-based regimens. However, these differences were not accompanied by detectable differences in cardiovascular outcomes.