Thyroid transcription factor-1 (TTF-1) is traditionally used to identify tumors of lung and thyroid primary. However, the specificity of this marker has recently come under increasing scrutiny as tumors from other organ systems are shown to also stain positively for TTF-1. On the basis of an index case of TTF-1-positive gastric adenocarcinomas, we evaluated a retrospective cohort (n=91) of these tumors for TTF-1 staining. Archived paraffin-embedded blocks of gastric adenocarcinoma cases from 2008 to 2013 were chosen for immunohistochemical staining. We report unexpected TTF-1 positivity in up to 25% of cases using the most sensitive TTF-1 clone SPT24. A subset of these cases also shows concurrent Napsin A positivity, including a case with lymph node metastasis, highlighting the potential for diagnostic confusion when dealing with metastatic disease of unknown origin. Because TTF-1 is not detected in the vast majority of cases using a separate antibody clone, 8G7G3/1, we conclude that aberrant staining is due to cross-reactivity to unknown antigen(s). TTF-1 positivity and even Napsin A positivity, therefore, cannot be used as conclusive evidence of pulmonary origin and gastrointestinal origin must be considered in the differential diagnosis.