The aim of this study was to determine the incidence and role of pentraxin-3 (PTX-3) overexpression as a predictive/prognostic marker in small-cell lung carcinoma (SCLC). We performed a retrospective study on subjects with a biopsy-proven diagnosis of SCLC. A chart review for demographic and clinical data was performed on patients with SCLC diagnosed between 2005 and 2008. PTX-3 overexpression was evaluated using immunohistochemistry performed on archival paraffin-embedded specimens. 125 patients with SCLC were identified (23 females, 102 males; median age 62.91±8.55 years, range 37-82) all of whom had adequate tissue specimens available for PTX-3 testing. High PTX-3 expression was detected in 25.6% SCLCs and was significantly associated with male gender and smokers. Moreover, elevated PTX-3 levels were correlated with reduced overall (OS) and disease-free survival, and were an independent negative prognostic factor for OS in SCLC. Our findings suggest that high PTX-3 expression appeared to correlate with aggressive behavior in SCLC, and it may be a useful prognostic marker for SCLC patients and a potential molecular target for SCLC treatment.