Anaplastic lymphoma kinase (ALK) rearrangements have been reported in 3-7% of non-small-cell lung cancers (NSCLC). ALK has been reported to be fused with a variety of genes in NSCLC. Significant clinical activity was achieved by ALK inhibitors in patients with NSCLC harbouring ALK translocations. We reported on a 48-year-old male Chinese patient with advanced lung adenocarcinoma harboring a novel ALK-LIMS1 who showed no response to crizotinib. The tissue was assayed by immunohistochemistry (IHC) for ALK and showed diffuse expression of ALK. Next-generation sequencing (NGS) was performed on the peripheral blood and tissue. The previous tumor tissue showed diffuse expression of ALK. Tissue and the later peripheral blood revealed a ALK- LIMS1 fusion. The patient failed to benefit from crizotinib (250 mg, twice a day), with a progression-free survival of two months. We identified a new ALK-LIMS1 fusion from an advanced lung adenocarcinoma which was primary resistant to crizotinib. Our case suggested that the coexistence of mutations and the non-dominant clone, as well as the rearrangement of ALK fusion, did not result in expressed ALK kinase domain that might lead to no response to ALK-TKIs.© 2023 Shi et al.