Introduction Recent randomized controlled trials (RCT) failed to demonstrate non‐inferiority of skipping IV tPA in patients with planned endovascular therapy (EVT). None of these studies included patients from the US due to regulatory challenges. Given practice patterns vary relative to Asia and Europe, we sought to address this topic using a validated alternative to RCTs, fuzzy regression discontinuity design (RDD). Methods From our prospectively maintained multi‐center registry we identified patients with LVO AIS treated with EVT with and without IV tPA treatment from 1/2018 ‐ 9/2021. We used the time cutoff for IV tPA as our discontinuity and assumed subjects on either side of the cutoff have markedly different probabilities of receiving the treatment but are similar in other relevant characteristics. The primary outcome was good functional outcome defined as 90‐day mRS 0–2 and it was compared between these two populations immediately adjacent to the cutoff using local linear regressions. Results Among 694 patients with LVO AIS who received EVT, median age was 69 [IQR 59‐79], 50%, were female, 44% White, 24% Black, and 14% Hispanic. 51% received IV tPA, with median onset to treatment time of 109 min [IQR 79‐160]. We observed a sharp drop (47%) in the probability of tPA around the cutoff time of 4 hours (allowing 30 minutes for in‐hospital evaluation), while there were no significant differences in other relevant features at the cutoff, validating the underlying RDD assumptions (Figure A). Overall, 33% of patients achieved good functional outcomes and there were no significant differences around the cutoff time (Figure B). In fuzzy RDD, there was no evidence of an association of receiving tPA with good functional outcome with regression discontinuity of only 1.0% (p = 0.98)There were no significant differences in rates of hemorrhage in patients treated with or without IV tPA (22% vs 21%, p = 0.68). Conclusions Our study provides the highest quality US‐based evidence supporting the findings of the outside US trials, demonstrating no benefit of skipping IV tPA in patients with planned EVT.