This study compared effects of plasma-activated medium (PAM) with effects of conventional clinical thermal therapy on both lung cancer cells and benign cells for management of malignant pleural effusion (MPE). For MPE treatment, chemotherapy, photodynamic therapy, and thermal therapy are used but caused systemic side effects, patient photosensitivity, and edema, respectively. Recent studies show that plasma induces apoptosis in cancer cells with minor effects on normal cells and is cost-effective. However, the effects of plasma on MPE have not been investigated previously. This study applied a nonthermal atmospheric-pressure plasma jet to treat RPMI medium to produce PAM, carefully controlled the long-life reactive oxygen and nitrogen species concentration in PAM, and treated the cells. The influence of PAM treatment on the microenvironment of cells was also checked. The results indicated that PAM selectively inhibited CL1–5 and A549 cells, exerting minor effects on benign mesothelial and fibroblast cells. In contrast to selective lethal effects of PAM, thermal therapy inhibited both CL1–5 and benign mesothelial cells. This study also found that fibroblast growth factor 1 is not the factor explaining why PAM can selectively inhibit CL1–5 cells. These results indicate that PAM is potentially a less-harmful and cost-effective adjuvant therapy for MPE.