Long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) play an important role in central nervous diseases; however, the exact expression and co-expressed profiles in human traumatic brain injury (TBI) are still unknown. Therefore, we investigated whole blood in 12 patients with TBI and 4 healthy controls to observe expression characteristics with different severity. We identified 3,035 lncRNAs and 1,204 mRNAs differentially expressed in the severe TBI group, 2,362 lncRNAs and 656 mRNAs in the moderate group, and 433 lncRNAs and 100 mRNAs in the mild group. Enrichment analyses showed 30 signaling pathways such as inflammatory and immune response pathways. Subsequently, a lncRNA-gene co-expression network was generated for 717 lncRNA-mRNA pairs and most of them with a positive correlation. Based on GSEA analysis, we found that TBI caused severe immune abnormality reflected on Th1, Th2, and Th17 cell differentiation deficiency. Finally, the expression of one upregulated and one downregulated lncRNA was validated in all three TBI groups, which was consistent with the microarray results. In summary, our results show that expression profiles of lncRNAs and mRNAs are significantly different in bloods from different severity TBI especially in immune response, providing novel insight for lncRNAs in human TBI.Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.