Background: Despite using identical evidence to support practice guidelines for lipid-lowering treatment in primary prevention of cardiovascular disease (CVD), it is unclear to what extent the 2018 American Heart Association/American College of Cardiology/Multisociety, 2016 US Preventive Services Task Force (USPSTF), 2020 Department of Veterans Affairs/Department of Defense, 2021 Canadian Cardiovascular Society, and 2019 European Society of Cardiology/European Atherosclerosis Society guidelines differ in grading and assigning levels of evidence and classes of recommendations (LOE/class) at a population level. Methods: We included 7262 participants, aged 45 to 75 years, without history of CVD from the prospective population-based Rotterdam Study. Per guideline, proportions of the population recommended statin therapy by LOE/class, sensitivity and specificity for CVD events, and numbers needed to treat at 10 years were calculated. Results: Mean age was 61.1 (SD 6.9) years; 58.2% were women. American Heart Association/American College of Cardiology/Multisociety, USPSTF, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society strongly recommended statin initiation in respective 59.4%, 40.2%, 45.2%, 73.7%, and 42.1% of the eligible population based on high-quality evidence. Sensitivity for CVD events for treatment recommendations supported with strong LOE/class was 86.3% for American Heart Association/American College of Cardiology/Multisociety (IA or IB), 69.4% for USPSTF (USPSTF-B), 74.5% for Department of Veterans Affairs/Department of Defense (strong for), 93.3% for Canadian Cardiovascular Society (strong), and 66.6% for European Society of Cardiology/European Atherosclerosis Society (IA). Specificity was highest for the USPSTF at 45.3% and lowest for European Society of Cardiology/European Atherosclerosis Society at 10.0%. Estimated numbers needed to treat at 10 years for those with the strongest LOE/class were ranging from 20 to 26 for moderate-intensity and 12 to 16 for high-intensity statins. Conclusions: Sensitivity, specificity, and numbers needed to treat at 10 years for assigned LOE/class varied greatly among 5 CVD prevention guidelines. The level of variability seems to be driven by differences in how the evidence is graded and translated into LOE/class underlying the treatment recommendations by different professional societies. Efforts towards harmonizing evidence grading systems for clinical guidelines in primary prevention of CVD may reduce ambiguity and reinforce updated evidence-based recommendations.