The clinical distinction between cancer and chronic pancreatitis is difficult in patients with pancreatic masses. To test whether detection of aberrant serum DNA could assist in this important differential diagnosis, we tested a panel of 12 microsatellitemarkers from chromosomes 17p, 17q, 13q, 9p, 5q, and 2p in the blood of 35 pancreatic cancer patients, 22 patients with chronic pancreatitis, and 20 healthy individuals. An average of 2.8 loss of heterozygosity (LOH) was found in 32 of 35 cancer patients of whom 30 (86%) had 2 or more LOH. LOH was also found in 7 of 22 pancreatitis patients but all these patients had only 1 LOH. No LOH was detected in healthy donors of comparable age. These data suggest that LOH analysis may be a substantial help for diagnosing pancreatic masses. An extension of the panel, perhaps in combination with a better selection of markers may further improve this assay.