Abstract Aims The aim of this study was to explore the association of pregnancy loss (PL) with the incidence of cardiovascular disease (CVD) and examine the extent to which this relation is mediated by subsequent metabolic disorders. Methods and results We followed 95 465 ever-gravid women participating in the Nurses’ Health Study II between 1993 and 2017. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of CVD, including coronary heart disease (CHD), and stroke, according to the occurrence of PL. A mediation analysis was conducted to explore the intermediating effect of subsequent type 2 diabetes, hypertension, or hypercholesterolaemia. During 2 205 392 person-years of follow-up (mean 23.10 years), 2225 (2.3%) incident CVD cases were documented. After adjusting for confounding factors, PL was associated with an HR of 1.21 [95% confidence interval (CI) 1.10–1.33] for CVD during follow-up. A similar association was observed for CHD (HR 1.20; 95% CI 1.07–1.35) and stroke (HR 1.23; 95% CI 1.04–1.44). The risk of CVD increased with the number of PLs [HR 1.18 (95% CI 1.06–1.31) for 1 and 1.34 (95% CI 1.13–1.59) for ≥2 times] and was greater for PL occurring early in reproductive lifespan [HR 1.40 (95% CI 1.21–1.62) for age ≤23 years, 1.25 (95% CI 1.09–1.43) for age 24–29 years, and 1.03 (95% CI 0.88–1.19) for age ≥30 years]. Hypertension, hypercholesterolaemia, and type 2 diabetes all explained <1.80% of the association between PL and CVD. Conclusion PL was associated with a greater CVD risk, independently of subsequent development of metabolic disorders.