Managing dyslipidemia can be challenging in patients with statin intolerance. We describe the lipid effects of icosapent ethyl 4 g/day (high-purity prescription omega-3 eicosapentaenoic acid) in two coronary artery disease patients with statin intolerance who were self-treating with fish oil dietary supplements. After initiating icosapent ethyl, improvements were noted in the first and second patients, respectively, in total cholesterol (-12%; -21%), LDL cholesterol (-3%; -24%), triglycerides (-34%; -16%), non-HDL cholesterol (-12%; -22%), the omega-3 index (+42%; +8%) and eicosapentaenoic acid levels (+275%; +138%). Icosapent ethyl was well tolerated with no adverse events reported. These cases demonstrated favorable lipid effects with prescription icosapent ethyl treatment that may help optimize the care of high-risk coronary artery disease patients with statin intolerance.