The aim of the ICARO-3 study was to evaluate whether intra-arterial treatment, compared to intravenous thrombolysis, increases the rate of favourable functional outcome at 3 months in acute ischemic stroke and extracranial ICA occlusion. ICARO-3 was a non-randomized therapeutic trial that performed a non-blind assessment of outcomes using retrospective data collected prospectively from 37 centres in 7 countries. Patients treated with endovascular treatment within 6 h from stroke onset (cases) were matched with patients treated with intravenous thrombolysis within 4.5 h from symptom onset (controls). Patients receiving either intravenous or endovascular therapy were included among the cases. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale (mRS), dichotomized as favourable (score of 0–2) or unfavourable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Included in the analysis were 324 cases and 324 controls: 105 cases (32.4 %) had a favourable outcome as compared with 89 controls (27.4 %) [adjusted odds ratio (OR) 1.25, 95 % confidence interval (CI) 0.88–1.79, p = 0.1]. In the adjusted analysis, treatment with intra-arterial procedures was significantly associated with a reduction of mortality (OR 0.61, 95 % CI 0.40–0.93, p = 0.022). The rates of patients with severe disability or death (mRS 5–6) were similar in cases and controls (30.5 versus 32.4 %, p = 0.67). For the ordinal analysis, adjusted for age, sex, NIHSS, presence of diabetes mellitus and atrial fibrillation, the common odds ratio was 1.15 (95 % IC 0.86–1.54), p = 0.33. There were more cases of intracranial bleeding (37.0 versus 17.3 %, p = 0.0001) in the intra-arterial procedure group than in the intravenous group. After the exclusion of the 135 cases treated with the combination of I.V. thrombolysis and I.A. procedures, 67/189 of those treated with I.A. procedures (35.3 %) had a favourable outcome, compared to 89/324 of those treated with I.V. thrombolysis (27.4 %) (adjusted OR 1.75, 95 % CI 1.00–3.03, p = 0.05). Endovascular treatment of patients with acute ICA occlusion did not result in a better functional outcome than treatment with intravenous thrombolysis, but was associated with a higher rate of intracranial bleeding. Overall mortality was significantly reduced in patients treated with endovascular treatment but the rates of patients with severe disability or death were similar. When excluding all patients treated with the combination of I.V. thrombolysis and I.A. procedures, a potential benefit of I.A. treatment alone compared to I.V. thrombolysis was observed.