BACKGROUND: Given the potential complications of prostate biopsies, it is sometimes reasonable in selected patients to make a non-tissue diagnosis of prostate cancer. Little is known about prevalence and factors associated with non-tissue prostate cancer diagnoses in the United States. METHODS: We identified 40 to 99-year-old prostate cancer patients with prostate specific antigen (PSA) ≥20 ng/ml from the 2010-2015 National Cancer Database. Associations were examined between non-tissue prostate cancer diagnosis and age, race, clinical T (cT) and M (cM) categories, PSA, and Charlson-Deyo Comorbidity Index (CCI) with multivariable analyses. RESULTS: Among 62,635 patients, 6.2% had a non-tissue diagnosis. The proportion of patients with non-tissue diagnoses increased with advanced age (from 0.9% in ages 40-49 to 44.0% in ages 90-99) and disease stage (cT and cM) and higher CCI and PSA level. Demographic and clinical characteristics statistically significantly associated (all P < .001) with non-tissue diagnosis in adjusted analyses were older age (OR = 24.24, 90 to 99 vs. 60 to 69 years), and higher cT (OR = 4.83; T4 vs. T1), cM (OR = 5.25, M1C vs. M0), CCI (OR = 2.07; 3+ vs. 0), and PSA levels (OR = 3.19, >97.9 ng/ml vs.20 to 39 ng/ml), as well as hormonal therapy (OR = 0.51, with vs. without). CONCLUSIONS: Non-tissue diagnosis of prostate cancer, while rare, is not outside normal clinical practice and is strongly associated with advanced patient age, higher clinical stage, multiple comorbidities, and very high PSA levels.