<p>The impacts of lipid abnormalities on the development of cardiovascular events (CVEs) in relation to the cardio-ankle vascular index (CAVI) have not been fully elucidated. We sought to determine whether the association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular outcomes varies depending on the CAVI status in patients at risk for cardiovascular disease (CVD). Of 5109 patients enrolled in the multicenter, prospective COUPLING study (CardiOvascUlar Prognostic coupLING Study in Japan), the present analyses included 4,569 patients (51% male; mean age 68.5  ±  11.4years) who had both CAVI and serum HDL-C measured at baseline and whose clinical outcomes could be followed. The primary outcome was a composite of major CVEs. We stratified the subjects into two groups based on their CAVI values: CAVI &lt; 9 (<i>n</i> = 2501) and CAVI ≥ 9 (<i>n</i> = 2068). The incidence of CVEs was compared between these groups and further analyzed by HDL-C levels. During a median follow-up of 5.0 years, 220 CVEs occurred. In the CAVI &lt; 9 subgroup, low HDL-C ( &lt; 40 mg/dL) was also associated with an increased CVEs risk (hazard ratio [HR] 1.79, 95% confidence interval [CI] 1.02–3.14, <i>p</i> = 0.044). In the group with CAVI &gt; 9, the risk of CVEs in patients with HDL-C &lt; 40 mg/dL was not significantly different from that in those with HDL-C &gt; 40 mg/dL (HR 0.64, 95% CI 0.33-1.24, <i>p</i> = 0.640). Low HDL-C ( &lt; 40 mg/dL) was associated with an increased risk of CVEs in patients with normal-to-borderline arterial stiffness (CAVI &lt; 9). Among the subjects at risk for CVD, the combination of CAVI &lt; 9 and HDL-C &lt; 40 mg/dL identified those with a residual risk of CVEs.</p><p></p>