Importance: Previous cohort and animal studies suggested the direct effect of fibroblast growth factor (FGF) 23 on inducing left ventricular hypertrophy (LVH). Therefore, it is hypothesized that, in patients with chronic kidney disease (CKD), elevated FGF23 results in death or cardiovascular disease (CVD) through LVH. However, the influence of LVH on this association has not been statistically explored. Objective: To quantify the mediational effect of LVH in the causal pathway from FGF23 to long-term adverse outcomes. Design: Prospective observational study of adults with CKD stages 2 to 4 from the Chronic Renal Insufficiency Cohort (CRIC) study enrolled between April 2003 and September 2008, followed through December 2018. Setting: Seven institutions in the United States. Paricipants: Our fully adjusted model included 2368 participants, all of whom had measurements of FGF23 by C-terminal assay (C-term FGF23), left ventricular mass index (LVMI) at one year, and covariates. Main Outcomes and Measures: Linear and Cox proportional hazards regression models were employed to investigate the association between C-term FGF23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). The fully adjusted model included inflammation biomarkers and the use of erythropoiesis-stimulating agents as covariates influencing the C-term FGF23 value. Mediation analysis was used within a counterfactual framework to decompose the effect of C-term FGF23 into natural direct and indirect effects. Results: Among 2368 participants (mean age: 57.7 years, 1252 men), the median C-term FGF23 level was 138.8 RU/mL (interquartile range: 93.3-221.2 RU/mL). LVMI was positively correlated with C-term FGF23. During a median of 12.0, 11.1, and 11.1 years, C-term FGF23 was associated with all-cause mortality (HR = 1.63, 95% CI: 1.25-2.13), AF (HR = 1.67, 95% CI: 1.18-2.37), and CHF (HR = 1.36, 95% CI: 0.97-1.90) when the highest quartile was compared to the lowest quartile. LVH mediated 7.3%, 11.7%, and 24.3% of the effect of C-term FGF23 on all-cause mortality, AF, and CHF, respectively. Conclusions and Relevance: The current study revealed that the contribution of the development of LVH played a lesser role in the pathway from increased C-term FGF23 to the development of long-term adverse outcomes than previously expected.