<h3>Purpose</h3> To investigate whether right ventricular failure was associated with impaired left ventricular (LV) unloading during Left Ventricular Assist Device (LVAD) speed optimization. <h3>Methods</h3> Patients with Heartmate (HM) 3 LVADs implanted between January 2016 and April 2021 who had undergone speed optimization using right heart catheterization within one year from the implant were identified. We included patients with inadequate LV unloading as demonstrated by a pulmonary capillary wedge pressure (PCWP) above 12mmHg. We grouped patients based on the presence of right ventricular (RV) failure, defined as a right atrial pressure (RAP) to PCWP ratio >0.8. We also studied the impact of left ventricular transmural pressure (LVTMP) as a surrogate for true LV preload. Mean changes with increased pump speed (per 100 RPM) in PCWP were determined by the generalized linear mixed model. Line plots were used to present the slope of PCWP. All the analyses were performed on Stata version 17.0 (StataCorp LLC, College Station, TX, USA). A p-value of <0.05 was considered statistically significant. <h3>Results</h3> Thirty-six patients were included in this study. The median age was 52.5±11.8, 86.1% were male, 77.8% were implanted as destination therapy, and the median number of RPM changes was 3.5. Patients with RA/PCWP>0.8 had a trend towards lower decrease in PCWP with pump speed increase compared to RA/PCWP ≤0.8 (-0.57 vs -0.72, P=0.06, Figure 1A). Reduced LVTMP, defined as PCWP-RAP ≤4 mmHg, was significantly associated with a decreased slope of PCWP reduction with LVAD speed (-0.44 vs -0.96, p=0.02, Figure 1B). <h3>Conclusion</h3> In patients with RV failure the unloading of the LV is impaired, likely due to reduced LVTMP which is a surrogate for true LV preload. The presence of RV failure should be taken into account in the optimization of the LV pressures with speed optimization in HM3 patients.