OBJECTIVES: This study aims to estimate long-term survival in transthyretin familial amyloid polyneuropathy (TTR-FAP) rare disease using data from the largest and oldest worldwide patient’s cluster as treatment comparative effectiveness is very scarce. METHODS: Registry data from the Portuguese TTR-FAP referral centres were merged encompassing Val30Met patients followed until Dec2015. Three different cohorts were compared: untreated patients with disease onset between 1969 and 1992 (n=945), liver transplant (LTx) with intervention at stage 1 (n=935) and disease modifying oral tafamidis treated stage 1 patients with less 65 years age (n=331). Kaplan-Meier survival estimates were obtained and Cox proportional hazards model with delayed entry were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted by sex, late-onset, disease duration and treatment. RESULTS: Untreated patients have a median survival of 11.57 years (95%CI: 11.19-11.87) and treated with LTx of 24.73 years (95%CI: 22.90-27.09). Median survival was not reached in the tafamidis group, with 10 years’ survival rate 95.67% (95%CI: 87.49%-98.54%). LTx (HR 0.12, 95%CI: 0.09-0.15) and tafamidis (HR 0.05; 95%CI: 0.02-0.14) are associated with increased survival, compared with untreated patients. Being a late-onset patient and disease duration at treatment initiation are risk factors associated with increased mortality. No significant statistical effect was found for sex. CONCLUSIONS: Whereas still considered poor, substantial increases in long-term survival of TTR-FAP patients have been observed over the last decades. Although with higher short-term mortality, LTx significantly improved long-term survival. Tafamidis is associated with higher survival though longer follow-up data is still needed. Shorter time between disease onset and treatment is associated with increased survival. In case of clinical progression under drug treatment it’s important to further assess how and when to cross-over to other options such as LTx in order to maximize long-term survival from sequential treatments, with patients in the centre of medical decision making.