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Simple Summary: Survivors of childhood brain tumors, because of the treatments they have undergone, have a greater risk of dying earlier from cardiovascular causes compared to the general population. The objective of this study was to evaluate differences between cardiovascular risk biomarkers and cardiopulmonary exercise test (CPET) results from childhood brain tumor survivors and healthy controls. We found worse CPET performance in survivors associated with higher endothelin-1 values compared to controls. Correlation analysis showed an inverse relationship between CPET results and leptin, emphasizing the role of radiotherapy as a possible cause in the genesis of a greater cardiovascular risk in survivors of childhood brain tumors. In recent decades, the improvement of treatments and the adoption of therapeutic protocols of international cooperation has led to an improvement in the survival of children affected by brain tumors. However, in parallel with the increase in survival, long-term side effects related to treatments have been observed over time, including the activation of chronic inflammatory processes and metabolic alterations, which can facilitate the onset of metabolic syndrome and increased cardiovascular risk. The aim of this study was to find possible statistically significant differences in the serum concentrations of early biomarkers of metabolic syndrome and in the results of cardiopulmonary exercise testing between survivors of childhood brain tumors and healthy controls. This is a prospective and observational study conducted on a group of 14 male patients who survived childhood brain tumors compared with the same number of healthy controls. The concentrations of early metabolic syndrome biomarkers [adiponectin, leptin, TNF-α, IL-1, IL-6, IL-10, endothelin-1, apolipoprotein B, and lipoprotein (a)] were measured and a cardiopulmonary exercise test (CPET) was performed. Results: Childhood brain tumor survivors performed worse on average than controls on the CPET. Furthermore, they showed higher endothelin-1 values than controls (p = 0.025). The CPET results showed an inverse correlation with leptin. The differences found highlight the greater cardiovascular risk of brain tumor survivors, and radiotherapy could be implicated in the genesis of this greater cardiovascular risk. [ABSTRACT FROM AUTHOR]