Follicular dendritic cells (FDCs) support the survival of follicular lymphoma (FL). Tumor necrosis factor alpha (TNFα) is overexpressed by FL cells and is critical in the development and maintenance of FDCs. We hypothesised that TNFα might be an ideal therapeutic target. We treated seven patients with relapsed/refractory FL with 8 weeks of etanercept, 25 mg SC on day 1 and 4 of each week. Patients without progression received 16 additional weeks of etanercept. All patients completed at least 8 weeks of etanercept and two patients completed 24 weeks. At the 8 week evaluation five patients had SD. Of the five with SD, two progressed at 9 and 12 weeks on therapy and the remaining three progressed between 12 and 24 weeks after initiating therapy. Minimal toxicity was observed. FDG-PET imaging demonstrated decreases in standardized uptake value (SUV) following treatment with etanercept in five patients. Further studies in FL targeting the microenvironment in conjunction with standard cytotoxic therapy are warranted.