In X-linked hypophosphatemia (XLH), PHEX gene variants lead to elevated FGF23 production, resulting in hypophosphatemia, osteomalacia, osteomalacia-related fractures, osteoarthritis, enthesopathy, spinal stenosis, and symptoms of pain, stiffness, and decreased physical function. Burosumab is an anti-FGF23 monoclonal Ab approved for XLH treatment. Randomized studies comparing oral phosphate/active vitamin D (Pi/D) to burosumab in adults are lacking. This analysis, which utilized real-world data from the prospective, Americas-based XLH Disease Monitoring Program (NCT03651505), evaluated the effectiveness of burosumab vs Pi/D, based on changes from baseline to the year 1 visit in serum phosphate, 1,25(OH)2D, PTH, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF), and Timed Up and Go performance outcome. Two cohorts of adults with XLH who either began burosumab between baseline and the year 1 visit (n = 65) or were on Pi/D (n = 74) at study entry and did not receive burosumab were included. Inverse probability of treatment weighting was employed to adjust for potential confounding due to baseline cohort differences. At the year 1 visit, mean (SE) change from baseline was significant for burosumab vs Pi/D in serum phosphate (0.78 [0.08] vs 0.15 [0.14] mg/dL; p < .001), 1,25(OH)2D (19.41 [3.39] vs 5.49 [3.43] pg/mL; p = .011), PTH (-13.82 [5.00] vs 11.79 [8.10] pg/mL; p = .006), WOMAC pain (-7.50 [2.34] vs 4.47 [3.23]; p = .004), WOMAC physical function (-5.68 [1.96] vs 6.77 [4.85]; p = .006), and WOMAC total (-7.78 [2.06] vs 3.15 [3.37]; p = .005) scores, PROMIS PF (1.51 [0.73] vs -1.64 [1.11], p = .018), and TUG (-1.19 [0.42] vs 0.55 [0.43] s, p = .011). A trend towards improved WOMAC stiffness was observed for burosumab (-10.16 [2.85] vs -1.79 [3.68]; p = .086). In this real-world analysis of adults with XLH, burosumab treatment was associated with improved biochemical parameters, pain, physical function, and mobility compared with Pi/D.