Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.