<p>Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an aggressive and molecularly heterogenous cancer with poorly defined treatment strategies. We aimed to (i) assess whether RB1 immunohistochemistry alone can prognostically stratify LCNEC, (ii) determine whether adding p53, p16 and/or cyclin D1 immunohistochemistry to RB1 improves prognostic stratification, and (iii) perform a systematic review of RB1 status as a predictive marker for guiding chemotherapy regimen selection for LCNEC. A tissue microarray containing 59 archival pure pulmonary LCNEC resections was used for immunohistochemistry. Recurrence free survival (RFS) and disease specific survival (DSS) data were retrospectively assessed. Tumor responses to platinum etoposide versus other chemotherapy regimens were used in a pooled analysis with published study data. RB1 loss on immunohistochemistry was identified in 58% of cases. Among the tumors with RB1 loss, 94% had mutant-pattern p53. In multivariable analyses, retained RB1 was independently associated with longer disease-free survival of patients with advanced stage disease (HR 0.27, 95% CI 0.11–0.64, <i>P</i> = 0.0031). The addition of p53, p16 or cyclin D1 for subgrouping did not improve prognostic stratification. Prior studies on association of RB1 status with differential response to chemotherapy regimens had contrasting results. Overall, we find that RB1 loss assessed via immunohistochemistry is a poor prognostic factor for advanced stage LCNEC, and therefore may aid in identification of carcinomas likely to have small cell carcinoma-like behavior.</p>