Aims: Long non-coding RNAs (IncRNAs) could be attractive circulating biomarkers for cardiovascular risk stratification in subjects at high ASCVD risk such as familial hypercholesterolemia (FH). Our aim was to investigate the presence of IncRNAs carried by HDL in FH subjects and to evaluate the associations of HDL-IncRNAs with lipoproteins and mechanical vascular impairment assessed by pulse wave velocity (PWV). Methods: This was a retrospective observational study involving 94 FH subjects on statin treatment. Biochemical assays, HDL purification, IncRNA and PWV analyses were performed in all subjects. Results: LncRNA HIF1A-AS2, LASER and LEXIS were expressed in HDL; moreover, HDL-IncRNA LEXIS was associated with Lp(a) plasma levels (p<0.01). In a secondary analysis, the study population was stratified into two groups based on the Lp(a) median value. The High-Lp(a) group exhibited a significant increase of PWV compared to the Low-Lp(a) group (9.23±0.61 vs 7.67±0.56, p<0.01). While similar expressions of HDL-IncRNA HIFIA-AS2 and LASER were found in the two groups, the High-Lp(a) group exhibited a significant downregulation of HDL-IncRNA LEXIS compared to the Low-Lp(a) group (fold change -4.4, p<0.0001). Finally, Lp(a) and HDL-IncRNA LEXIS were associated with PWV (for Lp(a) p<0.01; for HDL-IncRNA LEXIS p<0.05). Conclusions: LncRNA HIFIA-AS2, LASER and LEXIS were expressed in HDL; moreover, significant relationships of HDL-lncRNA LEXIS with Lp(a) levels and PWV were found. Our study suggests that HDL-IncRNA LEXIS may be useful to better identify FH subjects with more pronounced vascular damage.