Decision about liver transplant is difficult in Wilson disease (WD) with liver failure, especially with conflicting reports about new Wilson index (NWI). Therapeutic plasma exchange (TPE) can provide survival with native liver (SNL) in WD. This study was done to see the effect of TPE on outcome and identify factors for SNL. All cases of WD with liver failure (INR. ≥ 2.5) from prospectively maintained data were included for propensity score matching (PSM) to select TPE (n = 48) and no-TPE (n = 48) groups. Three sessions of TPE on three consecutive days were given to TPE group. One hundred fifty-nine cases were included in the PSM with NWI & hepatic encephalopathy (HE) grading as predictors. SNL was comparable (26 vs. 17 cases (OR 1.45, p = 0.05) when the analysis was done in the whole cohort of 96 patients. SNL significantly improved when performed in those with no to early HE: TPE group (24/37) versus no-TPE group (14/34) (OR = 1.70, p = 0.03). Kaplan-Meier survival curves were significantly (log rank 0.019) improved in the TPE group when analyzing in no to early HE. Lower INR (adjusted OR 0.47, 95%CI 0.28-0.79, p = 0.005) and TPE administration (adjusted OR 3.12, 95%CI 1.10-9.4, p = 0.032) at enrollment were independently associated with SNL. Lower NWI (adjusted OR 0.686, 95%CI 0.53-0.89, p = 0.005) at 96 h was independently associated with SNL. TPE is independently associated with improvement in SNL by threefold in patients with NWI ≥ 11 and no to early HE. Patients with advanced HE should be offered immediate liver transplant. After 3 sessions of TPE, NWI < 11 increases SNL by 32%. Hence, NWI should be maintained below 11 with more sessions of TPE.