OBJECTIVES New-onset diabetes mellitus (DM) may herald pancreatic cancer (PaC). We determined whether changes in body weight distinguished PaC-associated DM (PaCDM) from type 2 DM. METHODS Among Olmsted County residents, we identified 29 PaCDM and 43 type 2 DM subjects who had serial fasting blood glucose measurements, new-onset DM, and no cancer-specific symptoms at DM onset. We compared body weight (kg) and fasting blood glucose (mg/dL) at DM onset, 1 to 2 years before and at index date in the 2 groups. RESULTS Fasting blood glucose values were similar before and at the onset of DM. Before onset of DM, PaCDM and type 2 DM subjects had similar body weight (P = 0.80). However, at onset of DM, 59% of PaCDM subjects lost weight versus 30% of type 2 DM subjects (P = 0.02). At onset of DM, 56% of type 2 DM subjects gained weight versus 31% of PaCDM subjects (P = 0.04). By index date, PaCDM subjects lost more weight than type 2 DM subjects did (8.3 ± 8.3 vs 0.8 ± 4.8 kg, P < 0.01). CONCLUSIONS Although new-onset primary type 2 DM is typically associated with weight gain, weight loss frequently precedes onset of PaCDM. The paradoxical development of diabetes in the face of ongoing weight loss may be an important clue to understanding the pathogenesis of PaCDM.