Abstract Recently we reported differential miRNA signatures in blood cells of lung cancer patients and healthy controls. With the present study we wanted to investigate if miRNA blood signatures are also suited to differentiate lung cancer patients from COPD patients. We compared the expression of 863 human miRNAs in blood cells of lung cancer patients, COPD patients, and healthy controls. The miRNA pattern from patients with lung cancer and COPD were more similar to each other than to the healthy controls. However, we were able to discriminate lung cancer patients and COPD patients with 90.4% accuracy, 89.2% specificity, and 91.7% sensitivity. In total, 140 miRNAs were significant for the comparison COPD and controls, 61 miRNAs were significant for the comparison lung cancer and controls, and 14 miRNAs were significant for the comparison lung cancer and COPD. Screening target databases yielded over 400 putative targets for those 14 miRNAs. The predicted mRNA targets of three of the 14 miRNAs were significantly up-regulated in PBMCs of lung cancer patients compared to patients with non-malignant lung diseases. In conclusion, we showed that blood miRNA signatures are suitable to distinguish lung cancer from COPD.