We report the case of a 79-year-old male who had undergone surgery for a mucus-secreting, stage-III pancreatic adenocarcinoma 2 years previously, who was recently started on capecitabine monotherapy for radiographic local progression. He developed disorientation, asterixis, nausea and elevated serum ammonia (221 μmol/L) 48-72 hours after treatment onset with preserved liver function. After ruling out potential causes of encephalopathy and tumor progression by abdominal and brain CT scans, his symptoms were related by exclusion to the recently initiated treatment with capecitabine. Capecitabine discontinuation, onset of standard anti-encephalopathy measures, and intravenous hydration led to a rapid, complete resolution of symptoms with serum ammonia normalization.