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Purpose: Response-adapted treatment using early interim functional imaging with PET after two cycles of chemotherapy (PET-2) for advanced-stage Hodgkin's lymphoma (AS-HL) is the standard of care in several countries. However, the distribution of residual metabolic disease in PET-2 and the prognostic relevance of multiple involved regions have not been reported to date. Methods: We retrospectively analyzed data from all PET-2-positive patients included in HD18. Residual tissue was visually compared with reference regions according to the Deauville score (DS). PET-2 positivity was defined as residual tissue with uptake above the liver (DS4). PFS was defined as the time from staging until progression, relapse, or death from any cause, or to the day when information was last received on the patient's disease status and analyzed using Kaplan-Meier and Cox regressions. Comparisons were made between patients with 1–2 and >2 positive regions in PET-2 as well as patients without PET-2-positive regions randomized into comparator arms of HD18. Results: Between 2008 and 2014, 1964 patients with newly diagnosed AS-HL were recruited in HD18 and randomized following their PET-2 scan. Of these, 480 patients had a positive PET-2 and were eligible for this analysis. Upper and lower mediastinum in almost half of all patients: 230 (47.9%) and 195 (40.6%), respectively. 372 (77.5%) of patients have 1–2 positive regions in PET-2. 5y-PFS for patients with 1–2 regions was 91.7% (CI95: 88.7–94.6) vs. 81.8% (CI95: 74.2–90.1) for those with >2 regions with a corresponding hazard ratio (HR) of 2.2 (CI95: 1.2–4.0). Compared with patients without PET-2-positive disease receiving 6–8 cycles of chemotherapy, patients with 1–2 had a higher risk for a PFS event (HR 1.35; CI95 0.81–2.28), but it was not statistically significant (p=0.25). Patients with >2 PET-2-positive lesions had a significantly higher risk (HR 2.95; CI95: 1.62–5.37; p<0.001). Conclusion: PET-2-positive residuals of AS-HL are mostly located in the mediastinum, and a majority of patients have few affected regions. The risk of progression was twofold higher in patients with more than two positive regions in PET-2. [ABSTRACT FROM AUTHOR]