OBJECTIVES: Recent research has shown complex and indirect associations of disease and treatment-associated cancer symptoms with health-related quality-of-life (HRQoL) constructs (e.g., functioning and QoL). Evident from this work are the causal cascades of symptoms flowing to distal HRQoL outcomes, and that these pathways are often mediated by patient-reported fatigue. We developed models and tested their correspondence in 1^st line non-small cell lung cancer (NSCLC) and 3^rd line or greater metastatic breast cancer (mBC) settings. METHODS: Data come from two randomized clinical trials (RCTs) of 1st line locally advanced or metastatic NSCLC and a single one-arm clinical trial of 3^rd line or greater mBC. Structural equation modeling (SEM) of direct and indirect symptom effects on distal HRQoL outcomes was conducted using questionnaires included in these trials; the EORTC QLQ-C30 was supplemented with the EORTC QLQ-LC13 in the NSCLC RCTs and with the Brief Pain Inventory short form (mBPI-sf) in the mBC clinical trial. We ran and interpreted goodness-of-fit tests to evaluate the extent that hypothesized conceptual models corresponded with the observed data. Estimates of standardized direct, indirect, and total effects of symptom on HRQoL showed the relative strengths of the cascade path components. RESULTS: There was a logical and consistent ordering, and effect magnitudes, of the causal cascade path components across the NSCLC and mBC trials. Specifically, the effects of symptoms (e.g., pain, dyspnea, and appetite loss) on HRQoL (i.e., physical, role, cognitive, emotional, and social functioning as well as QoL) were mediated by fatigue. CONCLUSIONS: Corroborating across-trial and across-tumor results demonstrate the consistent mediating effect of fatigue which links disease and treatment-associated cancer symptoms to HRQoL. Evaluating only direct effects of symptoms on HRQoL will underestimate the patient symptom burden. Interpretation of causal cascades will better inform patients, families, and clinicians about the HRQoL consequences of the disease and treatment.