Objective <p>Identify and quantify physiological sources of variability in hyperpolarized ¹²⁹Xe gas-exchange MRI and present a dose-delivery workflow that promotes repeatable lung inflation and alveolar pressure during imaging.</p> Theory and methods <p>A modular ¹²⁹Xe dose-delivery and monitoring system was developed with two configurations: a remotely actuated flow/volume-monitoring device used to evaluate pre-dose lung inflation, and a pressure-sensing mouthpiece used with conventional delivery to estimate alveolar pressure during breath-hold. In Cohort A (<i>n</i> = 12), standard coaching was evaluated by quantifying how pre-dose lung volumes deviated from the target of functional residual capacity (FRC). In Cohort B (<i>n</i> = 14), ¹²⁹Xe spectroscopy under normal, Mueller, and Valsalva breath-hold maneuvers was used to quantify the extent to which alveolar pressure modulates RBC:Membrane (RBC:M) and RBC oscillation amplitude.</p> Results <p>In Cohort A, coaching drove subjects in 70% of tests to exhale below FRC prior to dose delivery. Reduced lung volume is known to increase membrane and RBC signals beyond healthy-reference ranges. In Cohort B, changing alveolar pressure inversely affected RBC:M; Mueller increased RBC:M by 4.4% and Valsalva decreased it by 7%. Both maneuvers reduced RBC oscillation amplitude by ~20–25% of the original amplitude.</p> Conclusion <p>Variations in lung inflation and alveolar pressure are significant drivers of variability in critical ¹²⁹Xe metrics. Integrating actuated delivery and real-time monitoring into dose delivery workflows offers a practical pathway to improving repeatability and standardization of quantitative spectroscopy and gas-exchange imaging.</p>