Malignant pleural effusion (MPE) signifies a poor prognosis for patients with lung cancer. For treating physicians, the primary goals are to achieve sufficient control of MPE and minimize invasive intervention. Recombinant human mutant tumor necrosis factor-alpha (rhu-TNF) has been used in the treatment of MPE. The aim of our research was to evaluate the efficacy and safety of rhu-TNF application via ultrasound-guided chest tube for the treatment of MPE. rhu-TNF was administered as a single dose to 102 patients with MPE caused by lung cancer, and dexamethasone (Dxm, 5 mg) was administered 30 minutes before rhu-TNF in 35 randomly selected patients in order test its ability to prevent side effects. The primary endpoint was the efficacy of the rhu-TNF treatment (disease response rate) and side effects (pain, fever, and flu-like symptoms), evaluated four weeks after instillation. The disease response rate of rhu-TNF treatment was 81.37%. Side effects included 13 (12.75%) patients complaining of flu-like symptoms, 15 (14.71%) with fever/chill, and 14 (13.73%) with chest pain. A significantly higher efficacy was observed for treatment with 3 MU versus 2 MU of rhu-TNF (P = 0.036), while the adverse effects were similar. There was no significant association between the dose of rhu-TNF and progression-free survival (P = 0.752). In conclusion, our study shows that intra-pleural instillation of rhu-TNF achieves sufficient control of MPE and minimizes invasive intervention.