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Objective: To identify the most common neurological and behavioral symptoms treated by medications in individuals with fragile X syndrome (FXS), factors associated with treatment variability, and difficulty in swallowing a pill. Method: A total of 1019 caregivers provided information about 1064 sons and 299 daughters with FXS in a US national survey. Caregivers reported (a) current use of medications for attention, anxiety, hyperactivity, mood swings, anger, depression, seizures, self-injury, or sleep; (b) perceived efficacy; and (c) difficulty in swallowing a pill. Results: Sixty-one percent of males and 38% of females were currently taking medication for at least 1 symptom. The most common symptoms were anxiety, attention, and hyperactivity. Treatments for attention and hyperactivity were common in childhood but declined substantially after the age of 18 years; anxiety treatment remained high in adults. Children perceived to be more impaired and children diagnosed or treated for autism were more likely to be taking medications. Caregivers considered most medications somewhat effective, but less than one-third rated current medication as “a lot” effective. Many children had difficulty swallowing a pill, but only 11% of adult males and 2% of adult females had a lot of difficulty. Conclusion: Symptom-based medication use is common in FXS, although response is incomplete and there is clearly an unmet need for medications with improved efficacy. The persistent use of medications to treat anxiety, mood, and behavior problems throughout adolescence and into the adult years suggests important outcomes when evaluating the efficacy of new medications.