Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial, which randomly assigned 8012 hypertensive men to special intervention (SI) or usual care. SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part because higher mortality was observed for SI compared with usual care participants in H-clinics, whereas the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic left ventricular hypertrophy using both an ecological analysis by previously reported C- or H-clinic groupings and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and usual care in left ventricular hypertrophy were larger for C-clinics compared with H-clinics (Sokolow-Lyon: -93.9 versus -54.9 μV, P=0.049; Cornell voltage: -68.1 versus -35.9 μV, P=0.019; Cornell voltage product: -4.6 versus -2.2 μV/ms, P=0.071; left ventricular mass: -4.4 versus -2.8 g, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared with HCTZ through 48 months and 84 months of follow-up. Our findings on left ventricular hypertrophy support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in the Multiple Risk Factor Intervention Trial.