Introduction: Malignant pleural effusion was encountered in about 8-15% of lung cancer patients at initial cancer diagnosis. The optimal therapeutic strategies for lung cancer with malignant pleural effusion (MPE) remain unclear. Case Description: In this study, we reported a case of lung cancer with MPE, which was successfully managed with a multidisciplinary therapeutic strategy. The patient initially received gefitinib for 4 months with excellent response and he underwent salvage thoracoscopic lobectomy and systematic lymphadenectomy. Pathological complete response was confirmed for the patient and he discontinued gefitinib but received 4 cycles of adjuvant chemotherapy instead. The patient is still alive without disease progression for 62 months after surgery. Conclusions: Combining targeted therapy, salvage surgery, and adjuvant therapy may be a promising treatment strategy for lung cancer with MPE harboring oncogene-targeted mutations.