Purpose <p>Caregivers of terminally ill cancer patients are acknowledged to be at a heightened risk for experiencing severe psychological distress. This study examines psychological distress in healthy parents (HPs) caring for both a partner in the end-of-life phase and dependent children and how the Family-SCOUT intervention affects their distress course.</p> Methods <p>This analysis utilized data from the multicenter, quasi-experimental, non-randomized, non-blinded Family-SCOUT intervention study. HPs were stratified into subgroups based on their partner’s survival status 12&#xa0;months after T0 (study enrollment) and their assignment to the intervention or control group. Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS) at T0 and at T2 (9&#xa0;months of follow-up). Threshold analysis, <i>t</i>-tests, repeated measures ANOVA, and effect sizes were conducted to evaluate data.</p> Results <p>HADS values were available from <i>n</i> = 63 HPs with a terminally ill partner and <i>n</i> = 262 HPs with a partner, who survived 12&#xa0;months or longer after T0. Overall, the groups were similar apart from the distribution of sex. Distress was high in all subgroups but was especially elevated for HPs with a terminally ill partner. The trajectory of distress was influenced by their partner’s survival status and their intervention group allocation. Distress decreased in all subgroups except for HPs with a terminally ill partner not receiving the intervention.</p> Conclusion <p>HPs with a partner in the end-of-life phase are an especially vulnerable subgroup<i>.</i> Family-SCOUT appears beneficial for even highly distressed subgroups, although further research on the cause and the course of their distress is essential.</p> <p>Trial registration.</p> <p>ClinicalTrials.gov, NCT04186923, 4th of December 2019, retrospectively registered.</p>