Background: KRAS mutation is the most common oncogenic alteration in lung adenocarcinoma and is detected in smokers and up to 15% of never smokers. The tumor suppressor LKB1 is commonly mutated in NSCLC and LKB1 mutations occur concurrently in 30% of KRAS mutant NSCLC. In murine models, KRAS mutant tumors with concurrent LKB1 loss did not respond to docetaxel/selumetinib treatment. Immune checkpoint blockade by anti-PD-1/PD-L1 monoclonal antibodies (MoAb) is being clinically evaluated. Clinical responses to these agents correlate with PD-L1 expression and smoking status. We aimed to determine the expression of LKB1, PD-L1 and PD-L2 in KRAS mutant NSCLC from smokers (KS) and never smokers (KNS). Methods: We evaluated the clinical and molecular characteristics of KRAS mutant NSCLC patients (pts) using an institutional database. We examined LKB1, PD-L1, PD-L2 tumor expression by immunohistochemistry (IHC). IHC was performed using the murine MoAbs Ley37D/G6 (LKB1), 9A11 (PD-L1) and 9E5 (PD-L2). LKB1 staining was scored as intact or lost, with any degree of expression qualifying as intact, PD-L1 positive if >5% of cells were stained and PD-L2 positive if >10%. Results: Between 8/09 and 1/14 we identified 514 KRAS mutant NSCLC pts (stage I 22%/II 10%/III 19%/IV 49%) of which 39 were never smokers (incidence 7.6%) We analyzed 114 pts with available tissue using IHC (30 KNS and 84 KS). LKB1 loss was detected in 29% of cases (95%CI, 21-38%) and was significantly less frequent in KNS pts (KS 34% vs KNS 13%; P= 0.035). KRAS transversion mutations were more frequent in KS vs KNS pts (78% vs 37%; P= 0.0001). LKB1 staining was intact in 95% of KNS pts with transition mutations. Pts with LKB1 loss had more metastatic sites and brain involvement (47% vs 24%, P= 0.0472). PD-L1 was expressed in 19% of KRAS mutant cases and PD-L2 in 45% and were inversely correlated (r=-0.86, P <0.0001). PD-L1/PD-L2 expression was not related to either LKB1 status or type of KRAS mutation. PD-L1/PD-L2 IHC 3+ vs 1+/2+ staining was more frequent in KS vs KNS pts (50% vs 20%; 40% vs 13% respectively). Conclusions: KRAS mutant NSCLC is a heterogeneous disease. Our findings may have implications for choosing KRAS mutant pts for ongoing trials of MEK and PD-1/PD-L1 inhibitors.