Background <p>Deflazacort and prednisone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle function and increase survival. Yet, the side effects are significant. To this end, questions remain around the choice of agent, dosing, timing and frequency. Moreover, many gene-based alternative options to steroids are now reaching the market or are progressing through clinical development. This prospective comparative cohort study compared the effects of prednisolone (Pred) and deflazacort (DFZ) on anthropometric parameters, quality of life (QoL), behavioral outcomes, motor function, muscle ultrasonography (US), and pulmonary function tests in ambulant boys with DMD.</p> Results <p>Thirty-one steroid-naïve patients were enrolled: 12 received Pred, and 19 received DFZ. Over 9 months, both groups showed significant weight gain without significant changes in height or BMI. DFZ patients consistently had higher QoL scores than those on Pred, though within-group changes were not significant. No group differences were observed in behavioral assessments. DFZ-treated patients demonstrated significantly better motor function, particularly in gait, Gower’s maneuver, and chair rising scores, as well as shorter times in motor tasks, indicating slower disease progression. Muscle US revealed no between-group differences in rectus femoris echogenicity or grading; however, DFZ patients had initially and follow-up thinner diaphragmatic muscles, possibly due to baseline disparities. Pulmonary functions were largely comparable, with only FEV1% (meant as forced expiratory volume in one second) showing improvement in the DFZ group. Cushingoid facies occurred more frequently with Pred.</p> Conclusions <p>DFZ may offer advantages over Pred in improving QoL, better motor functions outcomes, diaphragmatic US examination, and FEV1% in DMD. Regarding side effect profiles, cushingoid facies was reported more significantly in Pred users than in those receiving DFZ.</p>