PURPOSE: To characterize early left heart functional changes during short-term mavacamten use in a real-world obstructive hypertrophic cardiomyopathy (oHCM) cohort using serial strain-based echocardiography. METHODS: This observational cohort study included 37 patients with oHCM: 22 receiving mavacamten and 15 in the comparison group. Serial echocardiographic, clinical and laboratory data were collected at baseline and at 4, 12, and 30 weeks. GLS was assessed as the main imaging variable using two-dimensional speckle-tracking echocardiography, with GCS, GRS, and LA strain parameters evaluated as exploratory strain indices. LVOT peak gradients were evaluated. RESULTS: At week 30, compared with the comparison group, the mavacamten group had a greater reduction in the Valsalva-provoked LVOT gradient (between-group LSM difference, -51.18 mmHg; p < 0.001). The mavacamten group showed a more pronounced longitudinal change in GLS (-3.47%; p < 0.001). Left atrial reservoir strain (LASr) increased to a greater extent in the mavacamten group (5.82%; p < 0.001). Exploratory analyses suggested between-group differences in left atrial conduit strain (LAScd) and left atrial contractile strain (LASct) mainly at week 30. No significant between-group differences were observed in GCS or GRS at any follow-up time point. CONCLUSION: In this oHCM cohort, short-term mavacamten use was accompanied by larger reductions in LVOT gradients and greater changes in GLS than those observed in the comparison group. Exploratory analyses suggested corresponding changes in LA strain indices. Serial strain-based echocardiographic assessment may provide complementary information on short-term changes in left heart function during follow-up. These observations require confirmation in larger studies with longer follow-up.