Aim To investigate the effect of cumulative non-high density lipoprotein cholesterol/high density lipoprotein cholesterol (non-HDLC/HDLC) exposure on atherosclerotic cardiovascular disease(ASCVD). Methods A prospective cohort study was conducted. A total of 50 777 employees of Kailuan Group who participated in three physical examinations in 2006—7,8—2009 and 2010—2011 were selected as the study subjects. Groups were divided into Q1, Q2, Q3 and Q4 according to the cumulative non-HDLC/HDLC exposure quartiles. Kaplan-Meier curve was used to calculate the cumulative incidence of ASCVD in different cumulative non-HDLC/HDLC groups, and Log-rank test was used to compare the differences among groups. Cox proportional risk model was used to analyze the effect of cumulative non-HDLC/HDLC exposure on ASCVD. Results The average follow-up was (10.19±2.21) years, and 5 003 new cases of ASCVD occurred. The cumulative incidence of ASCVD in groups Q1 to Q4 was 6.49%, 8.71%, 10.86% and 14.85%, respectively(Log-rank P＜0.01). Multivariate Cox regression analysis showed that compared with group Q1, the HR(95%CI) of ASCVD in groups Q2, Q3 and Q4 were 1.13(1.03～1.24), 1.18(1.07～1.29), 1.22(1.12～1.34), respectively; the HR(95%CI) of myocardial infarction were 1.15(0.87～1.53), 1.44(1.10～1.88), 1.67 (1.29～2.17), respectively; the HR(95%CI) of revascularization were 1.21 (0.99～1.49), 1.31 (1.07～1.60) and 1.49(1.22～1.81), respectively; the HR(95%CI) of ischemic stroke were 1.17 (1.03～1.32), 1.17 (1.04～1.33) and 1.21 (1.06～1.37), respectively; but the above association was not found when heart failure and atrial fibrillation were used as the outcome events. The restricted cubic spline showed that cumulative non-HDLC/HDLC values were linearly associated with the risk of ASCVD. Conclusion Cumulative non-HDLC/HDLC exposure was positively associated with the risk of ASCVD.