Esophageal pressure (PEs) can be used to approximate pleural pressure (Ppl) and might be clinically useful, particularly in the obese e.g., to guide mechanical ventilator settings in critical illness. However, mediastinal artifact (the difference between true Ppl and PEs) may limit acceptance of the measurement, and reproducibility of PEs measurements remains unknown. Therefore, we aimed to assess the effect of body posture on PEs in a cohort of obese, but healthy subjects, some of whom had multiple measurements, to address the clinical robustness of esophageal manometry. Twenty-five overweight and obese subjects (BMI > 25 kg/m2) and 11 control lean subjects (BMI < 25 kg/m2) underwent esophageal manometry with pressures measured seated and supine. Twenty overweight and obese subjects had measurements repeated after ∼1 to 2 weeks. Anthropometric data and sitting and supine spirometry were recorded. The average end-expiratory PEs sitting and supine were greater in the overweight and obese group than the lean group (sitting −0.1 ± 2.1 vs. −3.3 ± 1.2 cmH2O, supine 9.3 ± 3.3 vs. 6.9 ± 2.8 cmH2O, respectively). The mean differences between repeated measurements were small (−0.3 ± 1.7 cmH2O sitting and −0.1 ± 1.5 cmH2O supine). PEs correlated with a number of anthropometric and spirometric variables. In conclusion, PEs are slightly greater in overweight and obese subjects than lean subjects; but changes with position are similar in both groups. These data indicate that mediastinal weight and postural effects on PEs are within a clinically acceptable range, and suggest that esophageal manometry can be used to inform clinical decision making across wide range of body types.