Despite the recent advances in cancer therapeutics for lymphoma (Lym), a continuum of disease, treatment and psychological challenges, adversely impacting health-related quality of life, remain for the clinical management of the patient with Lym. In response, this study presents the development and validation of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) Lymphoma Symptom Index-18 (FLymSI-18). Patients with advanced Lym (n = 50) rated the significance of 40 symptoms, and hematologist-oncologists (n = 10) rated these symptoms according to importance and disease-related or treatment-related origin. Patient symptom priorities were unified with clinician priorities for symptom measurement in Lym for instrument development. Reliability estimates indicate that FLymSI-18 has acceptable internal consistency (α = 0.87), content validity and concurrent validity as indicated by moderate to strong correlations with the FACIT (Functional Assessment of Chronic Illness Therapy). Overall, the FLymSI-18 provides evidence for its reliability and validity as a brief assessment of the most important symptoms associated with advanced Lym in the clinical trial research environment.