Hypophosphatasia (HP) is an inborn error of metabolism that is characterized by reduced bone mineralization. The aim of this investigation was to evaluate treatment of incapacitating lower limb pain in patients with childhood HP using nonsteroidal antiinflammatory drugs (NSAID). All patients (seven boys; age 32 months to 16 years) presented with delayed walking, the typical waddling gait, muscular weakness of the lower limbs, and a limited walking distance. Six patients had severe diffuse lower limb pain following physical activity and were therefore treated with NSAID. The benefit of this treatment was evaluated clinically and by measurement of renally (PGE2) and systemically (PGE-M) derived prostaglandins (PG) in urine before and during therapy. After treatment with NSAID all six patients showed marked clinical improvement with reduced pain, increased muscle strength, and a normalized walking distance. Levels of PGE-M, which had been elevated in four patients prior to therapy, returned to normal. The use of NSAID in childhood HP should be considered as a possible therapeutic approach because the quality of life in these patients is markedly impaired by pain of the limbs. Elevated PG might play a role in the bone metabolism of HP patients.