Introduction: Early neurological deterioration (END) is associated with poor outcomes in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). Causes of END after mechanical thrombectomy (MT) include unsuccessful recanalization and reperfusion hemorrhages. However, little is known about END excluding the aforementioned causes. We aimed to investigate factors associated with unexplained END (END_unexplained) with regard to the cerebral collateral status. Patients and Methods: Multicenter retrospective study of AIS-LVO patients with successful MT (mTICI 2b-3). On admission CT angiography (CTA), pial arterial collaterals and venous outflow (VO) were assessed using the modified Tan-Scale and the Cortical Vein Opacification Score (COVES), respectively. END_unexplained was defined as an increase in NIHSS score of ⩾ 4 within the first 24 hours after MT without parenchymal hemorrhage on follow-up imaging. Multivariable regression analyses were performed to examine factors of END_unexplained and unfavorable functional outcome (modified Rankin Scale score 3-6). Results: A total of 620 patients met the inclusion criteria. END_unexplained occurred in 10% of patients. While there was no significant difference in pial arterial collaterals, patients with END_unexplained exhibited more often unfavorable VO (81% vs. 53%; P < 0.001). Unfavorable VO (aOR [95% CI]; 2.56 [1.02-6.40]; P = 0.045) was an independent predictor of END_unexplained. END_unexplained was independently associated with unfavorable functional outcomes at 90 days (aOR [95% CI]; 6.25 [2.06-18.94]; P = 0.001). Discussion and Conclusion: Unfavorable VO on admission CTA was associated with END_unexplained. END_unexplained was independently linked to unfavorable functional outcomes at 90 days. Identifying AIS-LVO patients at risk of END_unexplained may help to select patients for intensified monitoring and guide to optimal treatment regimes.