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Background Heart failure (HF) has been increasing in prevalence, and a need exists for biomarkers with improved predictive and prognostic ability. GDF‐15 (growth differentiation factor‐15) is a novel biomarker associated with HF mortality, but no serial studies of GDF‐15 have been conducted. This study aimed to investigate the association between GDF‐15 levels over time and the occurrence of ventricular arrhythmias, HF hospitalizations, and all‐cause mortality. Methods and Results We used a retrospective case–control design to analyze 148 patients with ischemic and nonischemic cardiomyopathies and primary prevention implantable cardioverter‐defibrillator (ICD) from the PROSe‐ICD (Prospective Observational Study of the ICD in Sudden Cardiac Death Prevention) cohort. Patients had blood drawn every 6 months and after each appropriate ICD therapy and were followed for a median follow‐up of 4.6 years, between 2005 to 2019. We compared serum GDF‐15 levels within ±90 days of an event among those with a ventricular tachycardia/fibrillation event requiring ICD therapies and those hospitalized for decompensated HF. A comparator/control group comprised patients with GDF‐15 levels available during 2‐year follow‐up periods without events. Median follow‐up was 4.6 years in the 148 patients studied (mean age 58±12, 27% women). The HF cohort had greater median GDF‐15 values within 90 days (1797 pg/mL) and 30 days (2039 pg/mL) compared with the control group (1062 pg/mL, both P P =0.60) or 30 days (1173 pg/mL, P =0.78) and the control group. GDF‐15 was also significantly predictive of mortality (hazard ratio, 3.17 [95% CI, 2.33–4.30]). Conclusions GDF‐15 levels are associated with HF hospitalization and mortality but not ventricular arrhythmic events.