Background: As the population ages and cancer survival improves, the incidence of multiple primary cancers (MPC) is increasing. Several studies have documented poorer health outcomes among adults with MPC compared to single-cancer survivors. However, there is a paucity of research focused on understanding factors linking MPC to poor health outcomes and identifying individual (e.g., personality, sociodemographic, clinical) factors that increase risk. Purpose: The purpose of this study was to test a psychobehavioral stress-response model to identify factors associated with MPC health outcomes. We aimed to: 1) test the hypothesized model, examining linear relations among six latent variables: perceived stress, psychological response, behavioral response, financial toxicity, social health, and physical health; 2) explore associations between individual characteristics and upstream latent variables; and 3) describe self-management behaviors of MPC survivors. Methods: This cross-sectional study included MPC survivors recruited through a regional tumor registry whose first cancers (stages I-III) were diagnosed within 1-10 years. Data were collected via 1) a battery of validated questionnaires to measure latent variables and covariates; 2) tumor registry records; and 3) medical records. Structural equation modeling was performed to fit and modify the measurement model, specify the full SEM, and identify significant covariates. Descriptive statistics were conducted to characterize self-management. v Results: 211 participants completed questionnaires. Data fit a four-factor modified measurement model linking self-management, distress, financial toxicity, and functional health. Overweight BMI, graduate education, less neuroticism, and increased social support predicted better self-management. Poorer self-management, greater neuroticism, and lower social support predicted increased distress. Greater distress predicted financial toxicity. Greater distress and financial toxicity predicted poorer functional health. Scores for positive selfmanagement were generally high; obesity rates were above published norms. Conclusions: MPC survivors with higher risk BMI, less education, greater neuroticism, and lower social support should be considered at risk for poorer self-management and negative health outcomes. Self-management behaviors and distress are potentially modifiable intervention targets to reduce financial toxicity and improve functional health. Future research should evaluate the model with a focus on developing the science of MPC self-management and financial toxicity and include longitudinal assessments to identify critical times of increased vulnerability during MPC survivorship. vi