Identification of risk biomarkers may enhance early detection of smoking-related lung cancer. We measured between 392 and 1,162 proteins in blood samples drawn at most three years before diagnosis in 731 smoking-matched case-control sets nested within six prospective cohorts from the US, Europe, Singapore, and Australia. We identify 36 proteins with independently reproducible associations with risk of imminent lung cancer diagnosis (allp< 4 × 10−5). These include a few markers (e.g. CA-125/MUC-16 and CEACAM5/CEA) that have previously been reported in studies using pre-diagnostic blood samples for lung cancer. The 36 proteins include several growth factors (e.g. HGF, IGFBP-1, IGFP-2), tumor necrosis factor-receptors (e.g. TNFRSF6B, TNFRSF13B), and chemokines and cytokines (e.g. CXL17, GDF-15, SCF). The odds ratio per standard deviation range from 1.31 for IGFBP-1 (95% CI: 1.17–1.47) to 2.43 for CEACAM5 (95% CI: 2.04–2.89). We map the 36 proteins to the hallmarks of cancer and find that activation of invasion and metastasis, proliferative signaling, tumor-promoting inflammation, and angiogenesis are most frequently implicated.