Purpose: To evaluate the impact of the revised Nellix instructions for use (IFU) from 2016 on clinical outcomes and anatomic applicability by retrospectively applying them to a cohort treated with endovascular aneurysm sealing according to the original IFU 2013. Methods: A single-center study was conducted of 100 consecutive patients (mean age 72±8 years, range 46–91; 89 men) treated electively with standard bilateral EVAS from July 2013 to August 2015 and followed through December 2017. Procedures previously classified within and outside the original IFU from 2013 (75 and 25, respectively) were reclassified according to the revised IFU 2016 (34 and 66, respectively). Stepwise backward logistic regression analysis was performed to evaluate the prognostic value of specific anatomic features for the development of endoleak and/or migration. Results: The single most important morphologic feature disqualifying patients from being within IFU 2016 was a thrombus ratio >1.4 (36 of 41 reclassified patients). Overall technical success was 98% (100% within vs 97% outside IFU 2016, p=0.323) and 30-day mortality was 3% (0% within vs 5% outside IFU 2016, p=0.251). During a median follow-up of 31 months (range 0–53), overall mortality was 21% (15% within vs 24% outside IFU 2016, p=0.469); aneurysm-related mortality was 8% (3% within vs 11% outside IFU 2016, p=0.533). Twenty-six patients developed an endoleak (6 within vs 20 outside IFU 2016, p=0.172) and 23 had migration (4 within vs 19 outside IFU 2016, p=0.088). Both proximal neck length <10 mm and neck angulation >60° were positive predictors for the development of endoleak and/or migration. A reintervention was performed in 26 patients (7 within vs 19 outside IFU 2016, p=0.376). While a significant difference was found between the within vs outside IFU 2016 groups with regard to freedom from migration (p=0.026) and the composite freedom from endoleak and/or migration (p=0.021), there were no significant differences in survival (p=0.201) or freedom from reintervention (p=0.505), suggesting a limited effectiveness of the new IFU 2016. Conclusion: The IFU 2016 reduced the anatomic applicability to 34% from 75% for the original IFU 2013. The lack of significant intergroup differences in terms of survival and reinterventions suggests a limited effectiveness of the new IFU 2016.