There are limited data regarding the role of 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87%; end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.