Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by low activity of tissue non-specific alkaline phosphatase (TNSALP). HPP in adults has a heterogeneous clinical presentation, often with multiple musculoskeletal and systemic manifestations, which can lead to misdiagnosis and substantial delays in diagnosis. To better understand the most common clinical profile of adults with HPP, data from 270 adults with confirmed HPP diagnosis (≥18 year of age, low ALP and/or ALPL mutation) in the Global HPP Registry were analyzed. Most were women (75.2%) with a median age at enrollment into the registry of 50 years and a median ALP activity of 25 U/L (normal range: 40-150 U/L). Based on medical history, pain (74.8%), mostly described as chronic bone pain or generalized body pain, was the leading symptom reported. Dental manifestations, such as early loss of primary teeth, were reported in 60.4% of adults. Skeletal manifestations, such as recurrent and poorly healing fractures or pseudofractures, were observed in 47.8% of adults. A substantial proportion also reported fatigue (35.2%) and muscle weakness (26.3%). Of the adults who had quality of life data available, median (range) of SF-36v2 Physical Component Score was 42.4 (17.9, 63.3; n=203; population norm=50) and pain interference on the BPI-SF was 3.5 (0, 9.5; n=196; 0=does not interfere; 10=completely interferes). Most adults with available data (n=212) reported some disability on the HAQ-DI (66%). Of these 270 adults, 77 were treated with enzyme replacement therapy (asfotase alfa) while 193 had never received treatment. Demographics and baseline ALP activity were similar between ever and never treated adults. Treated patients had a higher occurrence of pain, dental issues, recurrent and poorly healing fractures or pseudofractures, fatigue, and muscle weakness compared with untreated patients. Generally, treated adults reported poorer quality of life before treatment initiation compared with untreated adults, though data were limited in treated adults. Of the patients treated, 61.0% had pediatric-onset HPP which likely reflects the indication for asfotase alfa in most countries; 29.9% had unknown onset. 57.5% of untreated adults had adult-onset HPP, 24.3% had pediatric-onset, and 18.1% has unknown onset. Pain, dental issues, fatigue, recurrent and poorly healing fractures or pseudofractures, and muscle weakness were the most frequently reported symptoms in both adults with pediatric- or adult-onset HPP. These results establish real-world clinical profiles of adults with HPP, both untreated and before treatment start. Similarities in clinical profiles between adults with pediatric-onset and adult-onset HPP suggest that the age at onset itself is of limited clinical utility; current clinical status and the degree of disability are likely more meaningful in making treatment decisions.