Gemcitabine therapy has been associated with radiation recall reactions when used in the treatment of carcinoma. We report four cases of hemodynamically significant pericardial effusion in patients with refractory lymphoma who were receiving gemcitabine, all of whom had a history of mediastinal radiation without subcarinal blocking. All four patients had pericardial abnormalities on echocardiography prior to receiving gemcitabine. Two patients required emergent surgical procedures. Of twenty other patients in our practice who received gemcitabine for refractory lymphoma without developing pericardial effusion, none had received prior direct radiation to the heart. The overall response rate of these 24 refractory lymphomas to gemcitabine-containing regimens was 46%. Although gemcitabine-based regimens have clear efficacy in refractory lymphoma, prior mediastinal radiation without subcarinal blocking may be a relative contraindication, especially in the presence of pericardial abnormalities on echocardiography. Physicians should be aware of the potential for developing a gemcitabine-induced radiation recall reaction resulting in hemodynamically significant pericardial effusion.