Objective: To report a case of metformin-associated exacerbation of chronic pancreatitis and examine this possible drug-disease interaction. Case Summary: A 59-year-old woman with chronic pancreatitis (CP) experienced a severe exacerbation of her characteristic chronic abdominal pain 3 weeks after initiation and titration of metformin therapy; the exacerbation resolved upon discontinuation of metformin. The patient presented to the emergency department experiencing nausea and severe right upper quadrant abdominal pain with radiation to the right flank. Persistent abdominal pain, which had been a primary feature of CP, was previously mild and easily controlled with oral analgesics. Laboratory studies ruled out acute pancreatitis and were significant only for elevated glucose (168 mg/dL). Subsequently, she was given intravenous pain and nausea medications and discharged to home. The pain and nausea shortly returned and continued for 3 more days, at which point she telephoned her gastroenterologist, who advised that she discontinue metformin because of possible adverse reaction. Within a few days of discontinuing metformin, the nausea resolved and abdominal pain gradually returned to baseline level. Discussion: Metformin is not generally known to cause or exacerbate pancreatitis, although cases of acute pancreatitis associated with metformin therapy have been reported in the literature. No cases involving chronic pancreatitis have been reported. Consequently, metformin's prescribing guidelines do not contain precautions or contraindications for patients with chronic pancreatitis. Use of the Naranjo probability scale for assessment of this case revealed that the adverse drug effect was possible, reflecting the symptomatic resolution upon discontinuation while accounting for the lack of causative certainty, previous conclusive case reports, as well as the presence of possible nondrug causes. Conclusions: To our knowledge, this is the first case describing metformin-associated exacerbation of chronic pancreatitis. Although this occurrence may be rare, cautionary consideration, education, and monitoring should accompany initiation of metformin therapy in select patients with chronic pancreatitis.