PAX (paired box) genes encode a family of transcription factors that regulate organogenesis and cell-lineage specification in multiple organ systems. In the pancreas, PAX proteins play a critical role in islet cell differentiation. We recently observed that islet cells show strong, diffuse staining for PAX8 by immunohistochemistry. However, PAX8 expression has not previously been examined in pancreatic endocrine tumors (PETs). The purpose of this study was to evaluate PAX8 expression in PETs, and to correlate expression with clinical and pathologic features and behavior. PAX8 expression in other well-differentiated neuroendocrine tumors (WDNETs) was also studied. In total, 190 tumors were evaluated: 156 primary WDNETs (63 PETs, 31 ileal, 5 duodenal, 5 gastric, 19 appendiceal, 13 rectal, and 20 pulmonary carcinoid tumors) and 34 liver metastases (18 PETs and 16 ileal carcinoid tumors). PAX8 was positive in 42/63 (67%) primary PETs. Expression of PAX8 was significantly associated with WHO category 1.1 ("benign" behavior) compared with category 1.2 (uncertain behavior) or 2 (well-differentiated endocrine carcinoma) (positive in 100%, 64%, and 52% of tumors, respectively; P<0.05). PAX8-positive PETs were also significantly smaller and more often clinically functional; PAX8-negative tumors were more frequently associated with liver metastases. PAX8 expression was not associated with patient age, gender, MIB1 index, or lymph node metastases. PAX8 expression was detected in 0/20 (0%) pulmonary, 1/5 (20%) gastric, 5/5 (100%) duodenal, 0/31 (0%) ileal, 4/19 (21%) appendiceal, and 11/13 (85%) rectal carcinoid tumors. Among the liver metastases, PAX8 was positive in 9/18 (50%) metastatic PETs compared with 0/16 (0%) metastatic ileal carcinoid tumors. In summary, PAX8 is expressed in normal pancreatic islet cells and in a high proportion of primary and metastatic PETs. In the GI tract, PAX8 is positive in the majority of duodenal and rectal carcinoid tumors, and in a minor subset of appendiceal and gastric carcinoids. PAX8 expression is absent in ileal and pulmonary carcinoid tumors. PAX8 immunostaining may be helpful in determining the primary site for a WDNET metastatic to the liver, as ileal (PAX8 negative) and pancreatic (PAX8 positive) tumors most often present as a metastasis from an occult primary. PAX8 may also be a prognostic marker in PETs, as loss of expression is associated with malignant behavior.