Background CalliSpheres® beads (CB) have been used recently for patients with hepatocellular carcinoma. However, the safety and effect of drug-eluting bead transarterial chemoembolization (DEB-TACE) in patients with stage III–IV lung cancer are still unknown. Purpose To evaluate the safety and efficacy of DEB-TACE with pirarubicin-loaded CB for the treatment of stage III–IV lung cancer. Material and Methods From July 2016 to April 2020, 29 patients with stage III–IV primary lung cancer underwent DEB-TACE with pirarubicin-loaded CB. The objective response rate (ORR) was the primary endpoint; the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results Twenty-nine patients received DEB-TACE with pirarubicin-loaded (median 60 mg) CB, with no severe adverse events or treatment-related deaths. After DEB-TACE, hemoptysis disappeared within 1–3 days in all patients, and the symptoms of cough or expectoration were significantly improved in 12 patients. ORR and disease control rate at one, three, and six months after DEB-TACE were 39.3% and 96.4%, 26.1% and 69.6%, and 29.4% and 58.8%, respectively. The median PFS was 6.3 months (range 1.1–30.1 months), and the three-, six-, and 12-month PFS rates were 70.2%, 50.1%, and 27.1%, respectively. The median OS was 10.2 months (range 1.1–44.6 months), and the three-, six, and 12-month OS rates were 87.9%, 68.6%, and 39.8%, respectively. Conclusion DEB-TACE with pirarubicin-loaded CB is safe, feasible, and well-tolerated for patients with stage III–IV lung cancer, and symptom control was a potential benefit of treatment.