This study assesses the risk of severe hyperlactatemia (defined as lactate levels > 4 mmol/L) in patients undergoing chronic low-dose aspirin (ASP) therapy and estimates the strength of this association. A case-crossover design was employed, in which individuals who experienced the outcome also served as their own controls, with exposure evaluated during a pre-event period. Additionally, a person-day–based analytical approach was used to compare exposure between case and control periods. Among the case group (ASP exposed/unexposed), the distribution was 127/578, while in the control group it was 547/3,968, yielding an odds ratio (OR) of 1.6 (95% CI: 1.29–1.97; z = 4.31; P < 0.0001). The findings suggest a modest association between low-dose aspirin use (100 mg/day) and elevated lactate levels, particularly in its primary indication for secondary prevention of vascular ischemic events. Although the observed risk is relatively low (OR = 1.6), clinical monitoring is advisable, especially when aspirin is co-administered with agents sharing similar toxicological profiles. Incorporating lactate level assessment into therapeutic management plans may enhance patient safety and therapeutic outcomes.