Background <p>Although high-sensitivity C-reactive protein (hs-CRP) and cumulative atherogenic index of plasma (CumAIP) are recognized risk markers for cardiovascular disease (CVD), their association with CVD incidence—and specifically their combined effect—in individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome is far less understood.</p> Methods <p>This study analyzed 3,028 participants at CKM stages 0–3 from the China Health and Retirement Longitudinal Study. Kaplan‑Meier survival curves and Cox proportional hazards models were used to investigate the associations of CumAIP and hs-CRP levels with the risk of CVD in this population, as well as to evaluate their combined effect on CVD incidence.</p> Results <p>During the 5-year follow-up period (2015–2020), 495 participants developed CVD. Both hs-CRP and CumAIP were associated with CVD risk. After progressively adjusting for all covariates, compared with the low-hs-CRP group, the high-hs-CRP group exhibited a 36.6% increased risk of CVD (HR = 1.366, 95%CI: 1.133 ~ 1.648); compared with the low-CumAIP group, the high-CumAIP group showed a 40.8% increased risk (HR = 1.408, 95%CI: 1.158 ~ 1.711). The combination of high hs-CRP and high CumAIP was associated with a higher risk of developing CVD. Compared to individuals with both low hs-CRP and low CumAIP, those with high levels of both biomarkers had a 1.834-fold higher risk (95%CI: 1.408–2.389). Subgroup analysis indicated that the combined association of hs-CRP and CumAIP was more pronounced in males.</p> Conclusion <p>This study suggests that elevated hs-CRP and CumAIP are jointly associated with CVD incidence, and their combination exhibits a joint effect among middle-aged and older adults with stage 0–3 CKM syndrome.</p>