Aims: Aspirin therapy for primary prevention of cardiovascular disease (CVD) is controversial, and guideline recommendations have changed throughout the last decades. We report temporal trends in primary prevention aspirin use among persons with and without diabetes and describe characteristics of incident aspirin users. Methods and results: Using Danish nationwide registries, we identified incident and prevalent aspirin users in a population of subjects ≥40 years without CVD eligible for primary preventive aspirin therapy from 2000 through 2020. Temporal trends in aspirin users with and without diabetes were assessed, as were CVD risk factors among incident users. A total of 522 680 individuals started aspirin therapy during the study period. The number of incident users peaked in 2002 (39 803 individuals, 1.78% of the eligible population) and was the lowest in 2019 (11 898 individuals, 0.49%), with similar trends for subjects with and without diabetes. The percentage of incident users with no CVD risk factors [diabetes, hypertension, hypercholesterolemia, or chronic obstructive pulmonary disease (a proxy for smoking)] decreased from 53.9% in 2000 to 30.9% in 2020. The temporal trends in prevalent aspirin users followed a unimodal curve, peaked at 7.7% in 2008, and was 3.3% in 2020. For subjects with diabetes, the peak was observed in 2009 at 38.5% decreasing to 17.1% in 2020. Conclusion: Aspirin therapy for primary prevention of CVD has decreased over the last two decades. However, the drug remained used in individuals with and without diabetes, and a large proportion of individuals started on aspirin therapy had no CVD risk factors.