The combination of gemcitabine with concurrent radiation therapy (Gem/RT) is a promising new approach that is being investigated in patients with unresectable pancreatic cancer. However, substantial toxicity with this combination has also been observed. This review was conducted to determine whether Gem/RT could be safely delivered in the neoadjuvant setting, based on our experience with this combined therapy in a cohort of patients with previously unresectable pancreatic cancer, who subsequently underwent surgical resection. Between July 1996 and June 2001, a total of 67 patients with locally unresectable pancreatic cancer, without distant metastatic disease, received Gem/RT at our institution. Seventeen patients (25%) underwent exploratory surgery following Gem/RT, and nine underwent standard Whipple resection. Thus 9 (52%) of 17 patients who had exploratory operations or 9 (13%) of 67 patients, underwent surgical resection. Thirty-day mortality after resection was 0%, and there were no major surgical complications. Median length of hospital stay was 14 days (range 11 to 19 days). With a median follow-up of 32 months, median survival for the resected patients was 17.6 months (95% confidence interval 12.6 to 37.3 months). Median survival for the remaining 58 patients was 11.9 months (95% confidence interval 9.6 to 14.7 months, P=0.013). We conclude that surgical resection may be safely performed after Gem/RT in a select group of patients initially considered to have unresectable pancreatic cancer. The use of Gem/RT in a neoadjuvant setting is currently being investigated in a multi-institutional phase II trial.