Osteopathic manual therapy (OMT) may reduce hyperinflation in patients with chronic obstructive pulmonary disease (COPD) by improving breathing mechanics. The aim of the study was to evaluate the immediate effects of OMT on hyperinflation in stable COPD patients with forced expired volume in 1s (FEV1) <50% predicted. Nineteen COPD patients of the median age 68 (IQR 63-72) years and the median FEV1 39.8 (IQR 33.4-46.6) % predicted were enrolled into the study. For the first session, patients were randomly assigned to either OMT or sham therapy. During the second session, the two groups of patients were crossed over. Pulmonary function and dyspnea were compared before and after both procedures. Neither pulmonary function nor dyspnea differed significantly before and after OMT or sham procedures. However, 36.7% and 47.4% patients achieved the minimally important difference for residual volume (RV) reduction after both OMT and sham therapy, respectively. Responders to OMT had a greater median (IQR) baseline sense of dyspnea compared to non-responders, assessed on a visual analog scale, of 7.0 (4.5-7.0) vs. 3.0 (0.0-5.0), p=0.040, respectively. Although OMT did not have an immediate effect on hyperinflation or dyspnea, a subgroup experienced a reduction in RV following OMT and sham therapy. Future studies are needed to identify the characteristics of responders.