OBJECTIVES: Approximately 1 in 200,000–335,000 people worldwide have homocystinuria (HCU) but it may be underdiagnosed. We examined incidence and prevalence of homocysteine (tHcy) testing and the frequency of tHcy levels >30 µmoles/L. METHODS: In the MarketScan^© Lab Database (MSN), we identified commercially insured patients with claims for a tHcy test (1/1/2006–3/31/2016). Frequency of elevated tHcy test result >30 µmoles/L and medications prescribed were examined. Frequencies of select comorbidities were assessed, using International Classification of Diseases (ICD-9 and ICD10) codes. Incidence of first-time tHcy testing and incidence and prevalence of tHcy >30 µmoles/L were tabulated. RESULTS: Of 8.2 million MSN patients in the Lab database, 1.9 million were enrolled throughout 4/1/15–3/31/16. Of those, 0.8% (15,012) had a tHcy test since 2006 (mean±SD, 10.8 ±±CONCLUSIONS: This study is one of the first to estimate the prevalence of tHcy levels in the range of classical HCU in the U.S. Of patients having many symptoms associated with classical HCU, few were diagnosed with a sulfur metabolism disorder. Such patients warrant further evaluation for etiology of their hyperhomocysteinemia, including screening for classical HCU.