Most patients with brain metastases have active extracranial disease, which limits survival unless effective systemic therapy can be administered. Available options have increased over the last 5 years. Therefore, we analyzed patient cohorts treated with or without systemic treatment after completion of whole brain radiotherapy (WBRT). This study included retrospective uni- and multivariate analyses of 189 patients. Two landmark analyses requiring minimum survival of 1 or 2 months from start of WBRT were performed. Age and Karnofsky performance status (KPS) requirements were also applied in order to resemble a prospective trial that would limit inclusion to patients with defined baseline characteristics such as adequate KPS. Irrespective of these different statistical scenarios, systemic treatment significantly improved survival. For example, the 2-month landmark analysis with upper age limit and inclusion of patients with KPS > 60 only showed median survival of 9.0 versus 3.7 months, p = 0.001. All patients alive after more than 2 years had received systemic treatment (chemotherapy, endocrine therapy, tyrosine kinase inhibitors or other drugs). After WBRT, systemic treatment is a prerequisite for long-term survival. The exact magnitude of improvement can only be assessed in randomized trials because retrospective cohort studies, even if carefully designed, are not able to correct for all potential imbalances.