Objective: In Europe there is a growing number of informal caregivers above 55 years of age, some of whom experience high levels of psychological distress. Our aim is to investigate the prevalence of psychological distress and its association with perceived mastery among elderly informal caregivers. Methods: In a large representative random sample of citizens from four cities in the Netherlands, we compared psychological distress among older and younger informal caregivers. Next, we selected informal caregivers aged 55 years and older (n = 2663). Mastery was measured by means of the Pearlin Mastery Scale and psychological distress by means of the Kessler psychological distress scale (K10). We presented weighted percentages and conducted multivariate logistic regression analyses. Results: The prevalence of psychological distress was 41.9% among elderly informal caregivers, as opposed to 52.6% among younger informal caregivers. Among the older informal caregivers there was an association between insufficient sense of mastery and psychological distress (OR = 21.3; 95% CI = 12.8–35.5), which persisted after correction for covariates (OR = 4.9; 95% CI = 2.8–8.6). Conclusion: The association between insufficient sense of mastery and psychological distress in elderly caregivers is strong. Mastery should be considered a point of engagement for preventive interventions on caregiver distress.