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For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with <i>GBA1</i> mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild <i>GBA1</i> variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe <i>GBA1</i> variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (<i>p </i>= 0.001). Subjects with heterozygous <i>GBA1</i> variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type <i>GBA1</i>, 4.9 (1.5–16), ng/mL (<i>p </i>= 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous <i>GBA1</i> carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory <i>GBA1</i> mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous <i>GBA1</i> carriers and wild type.