Abstract Background Although atrial fibrillation (AF) and heart failure (HF) have a similar cardiovascular risk profile, the differential associations of the risk factors with both disease are incompletely understood. Aim The aim of this study was to understand whether common clinical risk factors and cardiovascular biomarkers show different associations with incident AF and HF, and to investigate predictors of sequential disease onset and mortality. Methods In 58693 individuals free of AF and HF from European population-based cohorts, pooled multivariable Cox regression analysis was used to find predictors for AF, HF and all-cause mortality. P-values for differences between Hazard Ratios (HR) of risk factors for AF and HF were estimated using bootstrapping with 5,000 replications. When AF and/or HF were used in Cox regressions as explanatory variables, they were included as time-dependent variables. Results Median age was 50.5 years, 49.3% were men. Median follow-up time was 13.8 years with an all-cause mortality rate of 15.7%. Incident AF and HF was present in 5.0% and 5.4% of the participants, with 1.8% showing a sequential disease onset. In multivariable-adjusted models we observed stronger associations of body mass index (HR of 1.32 (95% CI 1.25–1.39) vs. 1.42 (95% CI 1.36–1.49), p=0.02), smoking (HR of 1.21 (95% CI 1.08–1.33) vs. 2.11 (95% CI 1.90–2.32), p<0.01) and antihypertensive medication (HR of 1.21 (95% CI 1.10–1.35) vs. 1.43 (95% CI 1.27–1.59), p<0.01) with incident HF than with incident AF. Total serum cholesterol (HR of 1.10 (95% CI 1.06–1.15), prevalent diabetes (HR of 3.46 (95% CI 2.60–4.32), high-sensitive C-reactive protein (HR of 1.12 (95% CI 1.08–1.16)) and glomerular filtration rate (HR of 0.92 (95% CI 0.85–1.00) were significantly related to incident HF but not AF. Age (HR of 1.54 (95% CI 1.47–1.61) vs. 1.54 (95% CI 1.47–1.62), p=0.95), male sex (HR of 2.87 (95% CI 2.42–3.33), p=0.13), prevalent myocardial infarction (HR of 1.65 (95% CI 1.26–2.04) vs. 1.75 (95% CI 1.36–2.11), p=0.73) and NT-proBNP (HR of 1.59 (95% CI 1.50–1.68) vs. 1.60 (95% CI 1.51–1.69), p=0.86) showed comparable associations with both diseases. Age, male sex, body mass index, total serum cholesterol, prevalent diabetes and NT-proBNP were all predictors of sequential disease onset after multivariable adjustment. In models including cardiovascular risk factors and NT-proBNP, the time-varying covariates incident AF and HF showed a strong association with all-cause mortality, with HR of 2.2 (95% CI 1.9–2.5) and 10.7 (95% CI 9.1–12.6), respectively. Sequential disease onset further increased the hazard ratio to 15.1 (95% CI 11.6–19.5). Conclusion In our pooled analysis of population-based cohorts, new-onset AF and HF showed different associations with common cardiovascular risk factors and biomarkers. Although both diseases significantly increased mortality, the highest risk was observed in individuals with sequential disease onset.