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BACKGROUND: Validated computable eligibility criteria use real-world data and facilitate the conduct of clinical trials. The Genomic Medicine at VA (GenoVA) Study is a pragmatic trial of polygenic risk score testing enrolling patients without known diagnoses of 6 common diseases: atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer. We describe the validation of computable disease classifiers as eligibility criteria and their performance in the first 16 months of trial enrollment. METHODS: We identified well-performing published computable classifiers for the 6 target diseases and validated these in the target population using blinded physician review. If needed, classifiers were refined and then underwent a subsequent round of blinded review until true positive and true negative rates ≥80% were achieved. The optimized classifiers were then implemented as pre-screening exclusion criteria; telephone screens enabled an assessment of their real-world negative predictive value (NPV-RW). RESULTS: Published classifiers for type 2 diabetes and breast and prostate cancer achieved desired performance in blinded chart review without modification; the classifier for atrial fibrillation required two rounds of refinement before achieving desired performance. Among the 1,077 potential participants screened in the first 16 months of enrollment, NPV-RW of the classifiers ranged from 98.4% for coronary artery disease to 99.9% for colorectal cancer. Performance did not differ by gender or race/ethnicity. CONCLUSIONS: Computable disease classifiers can serve as efficient and accurate pre-screening classifiers for clinical trials, although performance will depend on the trial objectives and diseases under study.