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Simple Summary: This study addresses the challenge of respiratory motion in pediatric patients undergoing proton therapy for total lymphoid irradiation (TLI), an essential component of reduced-intensity conditioning regimens for hematopoietic cell transplant (HCT) patients. The primary concern is the interplay effect, which can cause deviations from the planned dose during respiratory motion. The research utilized static and 4D CT images from ten patients to simulate the interplay effect and assess its impact on treatment planning. The study concludes that 4D plan evaluation and robust optimization techniques can help address respiratory motion challenges in proton TLI treatments, especially in cases where other motion management strategies like breath-holding are not feasible due to the patient's young age, the need for anesthesia, or medical conditions. Patient-specific respiratory motion evaluations are crucial to ensure adequate dosimetric coverage in proton therapy for pediatric patients. (1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized. [ABSTRACT FROM AUTHOR]