The positive effects of resilience on psychological distress has been found in previous studies in samples not including the seriously mentally ill. The present study aimed to investigate the course of psychological distress and resilience in the first two years of the Covid-19 pandemic in patients with severe mental illness (SMI) and major depressive disorder without psychotic features (MDD) compared to healthy control subjects. 141 patients with SMI or MDD who had been admitted to a psychiatric ward in Tyrol (Austria) or South Tyrol (Italy) in 2019 and 584 community controls participated in a longitudinal online survey. Next to collecting sociodemographic data, psychological distress was evaluated using the Brief Symptom Checklist (BSCL) and resilience by the 13-Item Resilience Scale (RS-13). Psychological distress was consistently significantly higher while resilience was consistently significantly lower among both patient groups compared to healthy controls. In the patient samples, those with MDD consistently exhibited a significantly higher prevalence and level of psychological distress and significantly lower resilience. Resilience had a moderating effect on psychological distress especially in the MDD group. Our results suggest that MDD patients represent a particularly vulnerable group and findings imply that these patients would profit the most from trainings fostering resilience.