BACKGROUND: A steroid treatment regimen that minimizes side effects and maximizes clinical benefits for Duchenne muscular dystrophy (DMD) is needed. Recent pre-clinical work assessed intermittent (once-weekly) low-dose steroids and reported benefits (decreased sarcolemmal injury) comparable to daily-dosing, but with less steroid-induced atrophy and greater impact on muscle performance (Quattrocelli, 2017). OBJECTIVE: To translate these preclinical findings, we determined the 12-month impact of low-dose, intermittent prednisone (0.75 mg/kg, twice-weekly) on the steroid-associated side-effect profile, muscle pathophysiology and function in DMD. We hypothesized that compared to standard daily-dosing, twice-weekly prednisone will produce a lesser impact on growth velocity, body mass index (BMI), DEXA-bone mineral density (BMD), and cortisol; but similar impact on efficacy as determined by function, serum creatine kinase (CK), magnetic resonance spectroscopy inflammation (MRS-T2) and fat fraction (MRS-FF) within the vastus lateralis muscle. The efficacy of daily-dosing on muscle pathophysiology was previously established as reduction in MRS-T2 by 3-4 ms and slowing of FF increase to 10% in 12-months (Arpan, 2014). METHODS: In this ongoing open-label exploratory study, steroid-naïve DMD boys (4-8 years) underwent a 12-month, twice-weekly prednisone regimen with assessments at baseline, 6 and 12 months. RESULTS: Six boys (5.3+1.4 years) completed the study without adverse effects or behavioral disturbances. Growth velocity was maintained (+5.9+1.1 cm, p<0.01) with no rapid rise in BMI (17.4+2.4 to 17.8+2.9) or change in DEXA lumbar z-score (-1.6+0.3 to -1.3+0.5) after 12-months and cortisol levels remained normal (>7 mcg/dL). Muscle MRS-T2 decreased by 3.1+1.6 ms (p<0.05) after 6 months, with no significant increase in MRS-FF after 12-months (8.1+8.0 to 8.2+7.8%). Serum CK (20,747+4648 to 13,130+5129 U/L, p=0.07) and 10-meter walk/run time (5.2+0.5 to 4.1+0.6, p=0.056) improved slightly. CONCLUSIONS: Preliminary findings suggest twice-weekly, low-dose prednisone in DMD does not result in side-effects associated with daily-dosing, and is effective in reducing muscle inflammation (MRS-T2) and slowing disease progression (MRS-FF). Ongoing comparison to natural history data will determine whether efficacy is similar to daily-dosing.