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Objective ROS1 fusions have been identified in 1–2% of non-small-cell lung cancer (NSCLC) patients; they are validated as a driver of carcinogenesis and could be subjected to inhibition by crizotinib. However, previous studies suggested a variable progression-free survival (PFS) ranging from 9.1 to 20.0 months for crizotinib treatment in ROS1-rearranged NSCLC. Here, we reported a 45-year-old female diagnosed with stage IVB lung adenocarcinoma with multiple lymph nodes and bone metastasis carrying a novel MPRIP-ROS1 fusion, which was identified by RNA-based NGS (next-generation sequencing) and was sensitive to crizotinib treatment. Materials and Methods A targeted NGS panel was used to analyze genomic DNA and total RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue block of the patient. An RNA fusion panel based on amplicon sequencing was designed for detection fusion variation. Fusion results were validated using reverse transcriptase polymerase chain reaction and Sanger sequencing. Results We reported a novel MPRIP-ROS1 fusion identified in this advanced lung adenocarcinoma case. The rearrangement was generated by exons 1–21 of MPRIP at chr17: p11.2 joined to exons 35–43 of ROS1 at chr6: q22.1, which retained an intact kinase domain of ROS1. The primary tumor and metastatic lymph nodes were eliminated on computed tomographic (CT) scan imaging after 2 months' crizotinib treatment, and the multiple bone metastatic lesions were significantly relieved according to bone scintigraphy images. To date, the treatment has lasted 16 months, and the patient is still in follow-up showing sustained response to crizotinib. Conclusion The study identified a novel MPRIP-ROS1 fusion that was sensitive to crizotinib, which provided a new driver of lung adenocarcinoma and potential therapeutic target for crizotinib. It also expanded NSCLC treatment of ROS1 rearrangement and highlighted the importance of genetic testing for precise treatment decision-making.