Introduction Several studies have investigated the association between non-statin lipid-lowering therapy and regression of atherosclerosis. However, the studies were mostly small and their results were not always robust. Objectives (1) to define if a dual lipid-lowering therapy (statin ± non-statin drugs) is associated with coronary atherosclerosis regression, estimated by intravascular ultrasound (IVUS); (2) to assess the association between dual lipid-lowering-induced changes in LDL-C and non-HDL-C levels and atherosclerosis regression. Methods We performed a meta-analysis including trials of non-statin lipid-lowering therapy, reporting C-LDL, non-HDL-C and total atheroma volume (TAV) with a minimum of 6 months of follow-up. The primary endpoint was defined as the change in TAV measured from baseline to follow-up, comparing groups of subjects on statins alone versus combination of statin and non-statin drugs. The random-effects model and meta-regression were performed. Results Eight eligible trials of non-statin lipid-lowering drugs (1759 patients) were included. Overall, the dual lipid-lowering therapy was associated with a significant reduction in TAV [−3.5 mm3 (95% CI: −4.5 to −2.6)]; I2=11%]. In the analysis stratified according to the lipid-lowering drug class (ezetimibe or PCSK9 inhibitors), the findings were similar. In a meta-regression, a 10% decrease in LDL-C or non-HDL-C levels, was associated, respectively, with 0.92 mm3 and 1.05 mm3 regressions in TAV. Conclusion Our data suggest the addition of ezetimibe or PCSK9 inhibitors to statin therapy results in significantly increased regression of TAV. When the LDL-C and non-HDL-C levels reached were lower, the observed effect was also greater. Forest Plot by Drugs Group Funding Acknowledgement Type of funding source: None