Adopting a personalized medicine approach beyond genetic/epigenetic profiling within psychiatric diagnostic and treatment is challenging. For the first time, we studied the influence of two patient resources (resilience and illness representation) on the success of an inpatient treatment of major depressive disorder (MDD). Using a 5-week observational real-world-study, the treatment- success was measured by the difference between the subjective depression- severity (according to the German short form of Beck’s Depression-Inventory) at baseline (i.e., days four to six post-admission) and study- endpoint. In the intention-to-treat sample (n = 60, 47.3 ± 12.8 years old; 58% females), the patients’ illness representation [measured by the “Krankheitskonzeptskala” (KK)] did not predict their treatment- success. The KK-dimension ‘trust-in-doctors’ was associated with resilience but not with the treatment-success. Albeit, the patients’ resilience (determined by Resilience- Scale, 11-item-version (RS-11)) negatively predicted their positive treatment- success (b = − 0.09, p = 0.017, f2 = 0.11). This influence of resilience on treatment- success was completely mediated by the baseline-depression- severity. This means, patients with low resilience reported high baseline-depression- levels which predicted a significant positive treatment- success. And, patients with high resilience reported low baseline-depression-levels which predicted no relevant or even negative inpatient treatment-success. The latter “high-resilience”- group (n = 27) was especially interesting. Remarkably, these patients appeared to have experienced within the first four-to-six inpatient treatment-days an “early sudden gain” against their considerable MDD- burden that initially had led to their admission. Thus, a stronger resilience might serve as a proxy of the development of an early MDD-relief as well as of lower baseline-depression- levels. Further studies are warranted to support the value of a patient’s resilience to predict his treatment response and inpatient treatment duration.