Identification of young patients with peripheral lymphadenopathy who will benefit from lymph node biopsy often is difficult. A model was developed to differentiate patients whose biopsy results do not lead to treatment (normal, hyperplastic, or benign inflammatory lymph nodes) from those whose biopsy results do lead to treatment (granulomatous or malignant nodes). The medical records and histopathology slides of 123 nine- to 25-year-old patients who underwent biopsies of enlarged peripheral lymph nodes were reviewed for pathological diagnosis and 22 clinical findings. Seventy-two (58%) patients had biopsy results that did not lead to treatment, and 51 (42%) had results that did lead to treatment. Using stepwise discriminant analysis, a predictive model was developed that assigned 95% of the cases to the correct biopsy group based on lymph node size; history of recent ear, nose, and throat symptoms; and chest roentgenogram. When tested prospectively on new patients, the model correctly classified 32 (97%) of 33. We conclude that this simple model can help select adolescents and young adults with peripheral lymphadenopathy for biopsy.