Background: Relapsed small cell lung cancer (SCLC) patients have limited treatment options and poor outcomes. NGR-hTNF is a vascular-targeting agent, which increases intratumoral chemotherapy penetration and T-lymphocyte infiltration. Methods: Twenty-eight patients relapsing after at least one platinum-based regimen with a treatment-free interval shorter (n = 16; platinum-resistant) or longer (n = 12; platinum-sensitive) than 3 months received NGR-hTNF 0.8 μg/m2 plus doxorubicin 75 mg/m2 every 3 weeks. The primary endpoint of this single-arm phase II trial was progression-free survival (PFS), and safety, response rate, and survival were secondary endpoints. Results: The most common grade 3–4 toxicities were neutropenia (53%) and anemia (21%). Median PFS was 3.2 months for all patients, 2.7 months for platinum-resistant patients, and 4.1 months for platinum-sensitive patients. Seven patients had partial responses (25%), including four (25%) with platinum-resistant and three (25%) with platinum-sensitive relapse. Mean changes from baseline in tumor burden (after two, four, and six cycles) did not differ between platinum-resistant (−9%, −29%, and −32%) and platinum-sensitive (−11%, −20%, and −43%) cohorts. Overall survival was associated only with baseline lymphocyte counts, with median survival times of 13.1 and 5.2 months for lymphocyte counts above or below the median, respectively. Conclusion: NGR-hTNF plus doxorubicin showed manageable toxicity and promising activity in patients with relapsed SCLC.