Background: In patients (pts) with advanced seminoma, efforts are underway to tailor a risk-adapted treatment strategy to the individual pt. Our main objective was to prospectively determine the prognostic value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT2) after two cycles of bleomycin, etoposide and cisplatin (BEP) or EP chemotherapy under standardized treatment and PET evaluation criteria. Methods: Pts with advanced-stage seminoma were treated with BEP or EP according to guidelines. PET/CT examinations were performed at baseline, after two cycles in all pts and after chemotherapy at physician’s choice. PET/CT response was qualitatively evaluated by two independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to the guidelines (at baseline, after treatment, during follow-up). The primary endpoint was the relapse-free survival (RFS). Results: From 01/2009 to 01/2017, 75 consecutive pts were enrolled, of whom 70 were evaluable. The clinical stage was IIA-B and IIC-III in 40% and 60% of the pts, respectively. Eight pts (11.4%) received consolidation radiotherapy. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these pts presented with stage IIC-III. The median follow-up was 79 months. Five-year RFS of PET/CT2-positive pts was 75% (95%CI: 60-95%) compared with 97.8% (95%CI: 93.7-100%) of PET/CT2-negative pts (p = .002). This significant improvement in RFS was maintained when analyzing only pts with clinical stage IIC-III (p = 0.04) and by excluding those who received consolidation RT (p = 0.02). An increasing linear association was found between the maximum diameter of retroperitoneal lymph nodes and the rate of PET/CT2+. In univariable Cox regression analyses, PET/CT2+ (HR: 12.9, 95%CI: 1.5-106.9, p = 0.02) and elevated HCG levels (HR: 6.3, 95%CI: 1.2-32.3, p = 0.03) were significantly associated with RFS, whereas IGCCCG risk group was not (p = 0.1). PET/CT2 result was also associated with the tumor shrinkage post-BEP (p = 0.009), whereas complete response at CT did not predict the RFS (p = 0.3). Conclusions: No residual FDG-uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, may outperform the utility of standard prognostic risk groups and may be more accurate to predict the RFS compared to standard response criteria. Benchmark RFS estimates for the design of the next clinical trials of chemotherapy de-escalation are offered.