Ventricular premature complexes (VPCs) may represent a reversible cause of heart failure (HF); however, the type of patients most prone remains unknown. This study leverages a large population-based database to examine interactions that might prove clinically useful in risk-stratifying patients with VPCs. We used the California Healthcare Cost and Utilization Project to identify patients with VPCs and incident systolic HF from January 1, 2005, to December 31, 2009. We calculated hazard ratios for predictors of incident systolic HF using multivariable Cox proportional hazard models. Interactions with known risk factors were studied. Of the 16.8 million patients experiencing 48.1 million hospitalizations, 35,817 (0.2%) had a VPC diagnosis and 198,818 (1.2%) developed systolic HF. Incidence of systolic HF was 62.8 per 1,000 patient-years (95% confidence interval [CI] 61.2 to 64.4) in those with and 6.1 per 1,000 patient-years (95% CI 6.1 to 6.2) in those without VPCs (p <0.001). After adjusting for potential confounders, VPCs were associated with a nearly twofold risk of systolic HF (HR 1.8, 95% CI 1.8 to 1.9, p <0.001). Interaction analyses revealed a stronger relation between VPCs and HF among those with fewer cardiovascular risk factors. A VPC diagnosis in younger patients (<65 years) without coronary artery disease, hypertension, diabetes, or atrial fibrillation exhibited a sixfold increased risk of systolic HF (HR 6.5, 95% CI 5.5 to 7.7, p <0.001). In conclusion, these results suggest that a diagnosis of VPCs independently predicts incident systolic HF. This effect is most pronounced in younger patients without co-morbidities, suggesting that VPCs may be an important cause of “idiopathic” HF.