Preliminary data suggest that secretagogin (SCGN), a calcium-binding protein identified from our previous proteomics study of colorectal cancers, is a potentially useful neuroendocrine marker. In this study, we further analyzed SCGN expression in normal and tumor tissues from various organ sites compared with three other conventional neuroendocrine markers [chromogranin A (CgA), neuron specific enolase, and synaptophysin]. We found strong SCGN staining in most normal neuroendocrine tissues except in the adrenal cortex. SCGN expression was identified in 140 out of 213 neuroendocrine tumors and 12 conventional carcinomas with neuroendocrine differentiation. In a subset of neuroendocrine tumors, such as gastric neuroendocrine cancers and typical carcinoid tumors of rectum and ovary, SCGN showed strong staining while CgA expression was often negative. It is intriguing to note that SCGN staining was positive in 26 out of 31 small cell lung cancers, more frequently than the other three markers. We conclude that SCGN is a novel neuroendocrine marker that may be useful in routine surgical pathology practice.