Background: This exploratory single-arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small-cell lung cancer (SCLC). Methods: Patients were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide 80–100 IV mg/m2 on days 1, 2 and 3 and cisplatin 60–80 mg/m2 IV on day 1 or carboplatin AUC 5–6 IV on day 1, every 21 days. The primary end points were overall survival (OS) and overall response rate to platinum regimen. Results: Twenty-six patients were enroled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1–9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, one patient (3.8%) had complete response and six (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrolment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse event from RRx-001 was mild discomfort at the infusion site (23%). Conclusions: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. Clinical trial registration: NCT02489903.