Background: Focal segmental glomerulosclerosis (FSGS) is a podocytopathy that is diagnosed based on characteristic histopathological lesions. Certain forms of FSGS with underlying genetic variants associated with the disease, including variants in podocyte proteins, as well as apolipoprotein L1 ( APOL1 ) risk alleles, and variants in collagen type IV (COL4) α3, α4, and α5 ( COL4A3-5 ) proteins, are typically resistant to current treatments. Methods: The DUPLEX clinical trial assessed the efficacy and safety of sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), in patients with biopsy-proven or genetic FSGS and demonstrated a greater antiproteinuric effect over 108 weeks compared to the active control irbesartan. This post hoc, exploratory analysis assessed the efficacy of sparsentan in the subset of patients enrolled in DUPLEX who had pathogenic variants in genes coding for podocyte proteins, COL4A3-5 variants, and APOL1 high-risk genotypes, altogether referred to as genetic FSGS (gFSGS). Results: Next-generation sequencing identified 31 patients with podocyte gene variants, 25 with COL4A3-5 gene variants, and 14 with APOL1 high-risk genotypes. Baseline characteristics varied between genetic subgroups, with slightly younger patients, on average, in the podocyte gene variant group, and more African American patients in the APOL1 high-risk genotype group. In this exploratory analysis, sparsentan treatment resulted in substantial and sustained proteinuria reductions and numerically more frequent complete remission of proteinuria compared with irbesartan, consistent with observations in the full DUPLEX study population. Moreover, a lower proportion of sparsentan- vs irbesartan-treated patients reached composite kidney endpoints. Conclusions: These findings support sparsentan’s antiproteinuric benefit in patients with gFSGS, a subgroup that is often resistant to other therapeutic interventions.