Introduction: Despite improvements in device technology, only one-third of stroke patients undergoing endovascular thrombectomy (EVT) achieve first-pass effect (FPE). We investigated the effect of arterial tortuosity and thrombus characteristics on the relationship between first-line EVT strategy and angiographic outcomes. Patients and methods: Patients with thin-slice baseline CT-angiography from the ESCAPE-NA1 trial (Efficacy and safety of nerinetide for the treatment of acute ischemic stroke) were included. Tortuosity was estimated using the tortuosity index extracted from catheter pathway, and radiological thrombus characteristics were length, non-contrast density, perviousness and hyperdense artery sign. We assessed the association of first-line EVT strategy (stent-retriever [SR] versus contact aspiration [CA] versus combined SR+CA) with FPE (eTICI score 2c/3 after one pass), final eTICI 2b/3, number of passes and procedure duration using multivariable regression. Interaction of tortuosity and thrombus characteristics with first-line technique were assessed using interaction terms. Results: Among 520 included patients, SR as a first-line modality was used in 165 (31.7%) patients, CA in 132 (25.4%), and combined SR+CA in 223 (42.9%). FPE was observed in 166 patients (31.9%). First-line strategy was not associated with FPE. Tortuosity had a significant effect on FPE only in the CA group (aOR = 0.90 [95% CI 0.83–0.98]) compared with stent-retrievers and combined first-line approach (p interaction = 0.03). There was an interaction between thrombus length and first-line strategy for number of passes (p interaction = 0.04). Longer thrombi were associated with higher number of passes only in the CA group (acOR 1.03 [95% CI 1.00–1.06]). Conclusion: Our study suggests that vessel tortuosity and longer thrombi may negatively affect the performance of first-line contact aspiration catheters in acute stroke patients undergoing EVT.