[(18)F]FDG-PET was found to be useful for recurrence detection in patients with oral squamous cell carcinoma (OSCC), as a negative PET scan predicted a favorable outcome and survival. Here, we evaluate PET performance in the management of OSCC patients with recurrent/second primary disease after potentially curative second-line therapy. Forty one OSCC patients underwent salvage surgery and 31/41 had received radiation therapy. Thirty five/41 developed recurrent and 6/41 second primary OSCC. Patients had PET evaluation 8.4months (median) after surgery and were followed for at least 6months until disease recurrence or death. For surviving patients, the median follow-up was 33.6months after PET. In OSCC patients who had undergone potentially curative second-line therapy, PET had an overall sensitivity of 85% (92% for recurrence or second primaries, 88% for lymph node failure and 73% for distant metastases). Overall survival was 71% in the PET negative group and 35% in the PET positive group (p<0.01, log-rank test). Moderate glucose metabolism (standardized uptake value4) suggested promising outcome, while SUV>4 indicated a fatal disease course. The data suggest that [(18)F]FDG-PET can facilitate re-staging and clinical management in "high-risk" patients with OSCC.