In order to identify anaplastic lymphoma kinase‐driven non‐small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK fusion variants V1, V2 and V3 as detected by next‐generation sequencing or reverse transcription‐polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4‐ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3‐driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3‐positive status was associated with earlier failure after treatment with first and second‐generation ALK TKI (median progression‐free survival PFS by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum‐based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first‐line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4‐ALK fusion variant V3 is a high‐risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies. What's new? EML4‐ALK fusions are driving 5% of non‐small cell lung cancers (NSCLC). The present study shows for the first time that a specific fusion variant, namely V3 (E6;A20), is associated with more aggressive disease and worse overall survival due to earlier failure of several therapeutic modalities. This will necessitate inclusion of molecular assays beyond FISH in future diagnostic guidelines for ALK+ NSCLC and prompt development of more efficient strategies for the management of higher‐risk, V3‐positive cases.