Background: Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Treatment options have not significantly changed over the past 3 decades and the 5-year survival has remained around 6%. Results of early phase human trials of immune checkpoint blockers are showing durable responses in about a quarter of patients. However, an immunologic characterization of SCLC is lacking. Based on recent results identifying Wnt/β-catenin pathway as a mechanism for immunotherapy resistance in melanoma, we pursued a similar analysis of immunologic gene signatures and molecular associations in SCLC. Methods: We first analyzed microarray expression data from 23 surgically resected tumors. Samples were classified into T cell-inflamed and non-T cell-inflamed groups using hierarchical clustering based on expression of 150 immune-related genes that show consistent expression across multiple tumor types including melanoma. Positive correlation between T cell transcripts and immune regulatory genes was investigated. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors. Results: 44% of tumors were classified as T cell-inflamed and 56% were non-T cell-inflamed. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p< 0.001). 200 genes were significantly upregulated in non-T cell inflamed tumors (fold change increase ranged from (2.7 to 37.7; FDR-adjusted p< 0.05). Evidence of activation of 4 pathways was found in the non-inflamed group including CTNNB1 (Wnt/β-catenin), MKNK1, NFE2L2 (which modulates response to oxidative stress) and NR3C1 (glucocorticoid receptor). Gene expression analysis of RNA-sequencing data a second dataset confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue. Conclusions: A large fraction of SCLC tumors show an immunologically active tumor microenvironment which suggests opportunity for immunotherapeutic interventions. Molecular pathways associated with T cell exclusion suggest new opportunities for targeted therapy that might synergize with immunotherapies.