Objective: Research links low marital quality to poor mental and physical health, but the impact of spousal infidelity on long-term chronic health, especially using longitudinal data, is understudied. The present work investigates whether infidelity predicted long-term chronic health, and whether demographic factors and support or strain from friends or family moderated this relationship. Methods: Using longitudinal data from 2579 adults from the United States (1093 males, 1486 females; Mage = 57.17, Medianage = 56, SDage = 12.26, age range: 33–84 years), we examined associations between partner infidelity and chronic health conditions across two timepoints (T1: 2004–2006, T2: 2013–2014). We analyzed participants’ history of partner infidelity at T1 and its relationship with chronic health through mixed models as well as latent variable structural equation modelling. We also examined whether supportive relationships and demographic variables moderated these associations. Results: Controlling for demographic covariates (age, gender, education, ethnicity, employment, marital status, marital satisfaction and income level), infidelity was linked to poorer chronic health in mixed model analyses ( p < .001), and this finding was also supported in latent variable analyses that controlled for baseline chronic health ( p = .003). Additionally, moderation analyses found that the impact of infidelity on chronic health was larger among low-income individuals and ethnic minorities. Conclusion: Partner infidelity has lasting detrimental associations with chronic health that are not mitigated by positive relationships. The research highlights the potential long-term health implications of partner infidelity and suggests the need for interventions to mitigate such negative effects.