Purpose <p>Pulmonary arterial hypertension (PAH) induces chronic pressure overload on the right ventricle (RV), driving remodeling, while the left ventricle (LV) remains largely preserved. The interventricular septum is often modeled as part of the LV; however, its role as a mechanically adaptive structure during PAH progression remains poorly understood. This study investigates full-thickness septal tissue mechanics in male and female rats.</p> Methods <p>RV and LV hemodynamics, septal morphology, and planar biaxial septum mechanical properties were measured in normotensive controls and rats at Weeks 4,&#xa0;8, and 12 of pulmonary hypertension using the sugen-hypoxia (SuHx) rat model of PAH. Biaxial stress-strain data were fit with an exponential Fung-type constitutive model for quantitative comparison across groups.</p> Results <p>RV hemodynamics varied by both sex and disease stage, while LV hemodynamics only showed sex differences (males had larger LV volumes). Despite similar RV end-systolic pressures, septal adaptation was sex-specific. Septal tissues exhibited nonlinear, nearly isotropic mechanical behavior. Starting from the same baseline stiffness, female septal tissues became significantly more compliant at Week 4, while male septal tissues remained unchanged. By Week 8, the females returned to baseline stiffness, while the males hit their peak compliance. By Week 12, male and female septa converged to similar stiffnesses.</p> Conclusion <p>Septal mechanical properties adapt during RV pressure overload, becoming more compliant with advancing RV remodeling. The degree and timing of remodeling are sex- and disease&#xa0;stage-dependent. These distinct patterns suggest septal mechanics play a functional role in modulating RV-LV interaction and support the need to treat the septum as an independent structure contributing to both chambers.</p>