Background <p>Childhood cancer survivors (CCS) often experience cancer treatment-related cardiotoxicity, leading to reduced cardiorespiratory fitness (CRF), an integrated marker of cardiovascular, respiratory, and musculoskeletal function. Furthermore, low CRF is a strong predictor of mortality.</p> Objective <p>This study investigates the effects of a 16-week aerobic exercise intervention on CRF changes, as measured by peak oxygen consumption (VO_2peak) and parameters of cardiac structure and function by cardiac magnetic resonance imaging (CMR).</p> Methods <p>Anthracycline-treated CCS were enrolled &gt; 2 years post-treatment and underwent cardiotoxicity risk stratification, cardiopulmonary stress test (CPET) to determine CRF, and CMR before and after a 16-week aerobic exercise intervention. The intervention consisted of individualized sessions performed 3–5 days per week, with duration progressively increasing from 15 to 45&#xa0;min at 50–80% of age-predicted maximal heart rate. Exercise adherence and intensity were objectively measured throughout the intervention using a Fitbit tracker. Subclinical myocardial dysfunction was assessed by segmental strain abnormality, with specific focus on the number of segments showing peak circumferential strain magnitude (εcc) ≤ 10% and εcc ≤ 17%. Descriptive and comparative statistics, including Pearson’s correlation and chi-square/Fisher’s exact and Mann-Whitney tests, were performed using SAS 9.4, with significance set at <i>p</i> &lt; 0.05.</p> Results <p>Forty-seven subjects (median age 22.0 years [IQR 8.5], 10–25 years), 57.4% male, and 75% white were enrolled. Thirty patients (63.8%) completed the exercise intervention, 56.7% male, and 83.3% white, with a median age of 24.0 years (IQR 9.8 years). Twenty participants (42.6%) met the predefined adherence criterion of achieving ≥ 100% of the prescribed fairly active plus very active minutes. There was no statistically significant change in VO_₂peak (mL/kg/min) for the study cohort (median [IQR]: 34.0 [13.7] vs. 34.4 [13.3]; <i>p</i> = 0.76). Total active minutes were positively correlated with change in VO_2peak (mL/kg/min) (<i>r</i> = 0.71, <i>p</i> &lt; 0.005), and VO_2peak (L/min) (<i>r</i> = 0.64, <i>p</i> = 0.03). VO_2peak increased <i>≥</i> 1 mL/kg/min in 16/30 (53.3%) of subjects. These subjects labeled “responders”, demonstrated a median increase in VO_2peak of 3.6 mL/kg/min and significant increase in right ventricular end diastolic volume index (<i>p</i> = 0.035), left ventricular stroke volume index (<i>p</i> = 0.014) and ejection fraction (EF) (<i>p</i> = 0.045). At baseline, 12 subjects met high-risk definition based on segmental strain abnormalities (i.e., ≥ 2 segments with εcc ≤ 10% or ≥ 9 segments ≤ 17%). High risk subjects showed significant improvement in εcc with a post-intervention reduction in number of segments ≤ 10% from 2.0 to 0.0 (<i>p</i> = 0.017).</p> Conclusions <p>Overall CCS did not show a significant change in VO_₂peak in response to a 16-week exercise intervention. Those with higher adherence to the exercise prescription were more likely to experience meaningful improvements in post-intervention VO_2peak and improvement in CMR parameters of structure and function. Participants classified as high-risk, based on εcc abnormalities, derived the greatest benefit.</p> Trial registration <p>Retrospectively registered: <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04036032">https://classic.clinicaltrials.gov/ct2/show/NCT04036032</a>, Registration date: July 25, 2019.</p>