Aim: Thiopurine S-methyltransferase (TPMT) testing is used in patients receiving thiopurines to identify enzyme deficiencies and risk for adverse drug reactions. It is uncertain whether genotyping is superior to phenotyping. The objectives were to conduct a systematic review of TPMT-test performance studies. Materials & methods: Electronic and grey literature sources were searched for studies reporting test performance compared with a reference standard. Sixty-six eligible studies were appraised for quality. Results: Thirty phenotype–genotype and six phenotype–phenotype comparisons were of high quality. The calculated sensitivity and specificity for genotyping to identify a homozygous mutation ranged from 0.0–100.0% and from 97.8–100.0%, respectively. Conclusion: Clinical decision-makers require high-quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients.