Background: Incomplete response on FDG PET-CT following (chemo)radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC) hinders optimal management. The study assessed the utility of an interval (second look) PET-CT. Methods: Patients with oropharyngeal squamous cell carcinoma cancer (OPSCC) treated with CRT at a single centre between 2013 and 2020 who underwent baseline, response, and second-look PET-CT were included. Endpoints were conversion rate to complete metabolic response (CMR) and test characteristics of second-look PET-CT. Results: In total, 714 patients with OPSCC underwent PET-CT post-radiotherapy. In total, 88 patients with incomplete response underwent second-look PET-CT a median of 13 weeks (interquartile range 10–15 weeks) after the initial response assessment. In total, 27/88 (31%) second-look PET-CTs showed conversion to CMR, primary tumour CMR in 20/60 (30%), and nodal CMR in 13/37 (35%). In total, 1/34 (3%) with stable tumour/nodal uptake at the second-look PET-CT relapsed. Sensitivity, specificity, positive (PPV), and negative predictive value (NPV) of second-look PET-CT were 95%, 49%, 50%, and 95% for tumour and 92%, 50%, 50%, and 92% for nodes, respectively. Primary tumour progression following CMR occurred in one patient, two patients with residual nodal uptake at second-look PET-CT progressed locoregionally, and one patient developed metastatic disease following CMR in residual nodes. Conclusion: Most patients undergoing second-look PET-CT converted to CMR or demonstrated stable PET signal. NPV was high, suggesting the potential to avoid unnecessary surgical intervention.