Abstract High Id1 levels have been found in some tumor types, particularly in advance stages. We aimed to study Id1 levels and their prognostic value in a large series of different histologies of stage I-IV NSCLC patients and to test Id1 function in cell lines and cells derived from malignant pleural effusions (MPE) from patients (pts). Id1 expression was analyzed in NSCLC samples from 311 pts and 65 normal lung tissues by immunohistochemistry. Id1 mRNA expression was also studied in 111 pts using publicly available microarrays. Significantly higher Id1 protein expression levels were found in tumors compared to normal tissue (p<0.001) and in adenocarcinomas (AC) compared so squamous histology (p<0.001). Among the localized NSCLC pts undergoing surgery, higher Id1 expression levels were associated with a shorter overall survival (OS) for AC histology (p=0.017). In the surgery+adjuvant chemo-radiotherapy pts, the same correlation was found between Id1 levels and OS among AC samples (p=0.038). Consistently, in stage IV pts receiving palliative chemotherapy, Id1 maintained its prognostic value (shorter OS in pts with higher levels) for AC (p=0.003). Id1 was also correlated with time-to-progression (TTP) after chemotherapy (lower levels, prolonged TTP) in AC pts (p=0.008). The in silico analysis confirmed this association. High expression of Id1 was also found by western blots in squamous cell lines (H520, HCC15, H157 and H58) and in lesser extent in AC cell lines (SKLU-1, LXF-289, H322, H23) and MPE-derived AC cells. Id1 knockdown resulted in a significant reduction of the clonogenic activity of squamous and AC cells. Id1 silencing on radiotherapy and chemotherapy-resistant MPE-derived cells restored sensitivity to both therapies. We conclude that Id1 protein and mRNA expression is an independent prognostic factor among pts with AC but no other histologies, regardless of the stage or treatment received. In cell lines derived from MPE pts, Id1 downregulation decreases NSCLC cell proliferation and sensitizes cells to radiotherapy and chemotherapy, in vitro. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2011-2219