Background: Despite improvement of tumor response rates, targeted therapy may induce toxicities in cancer patients. Recent studies indicate amelioration of adverse events (AEs) by add-on mistletoe (Viscum album L., VA) in standard oncological treatment. The primary objective of this multicenter observational study was to determine the safety profile of targeted and add-on VA therapy compared to targeted therapy alone. Methods: Demographic and medical data were retrieved from the Network Oncology registry. Allocation to either control (targeted therapy) or combinational group (targeted/add-on VA) was performed. Safety-associated variables were evaluated by adjusted multivariable analyses. Results: The median age of the study population (n = 310) at first diagnosis was 59 years; 67.4% were female. In total, 126 patients (40.6%) were in the control and 184 patients (59.4%) in the combination group. Significant differences were observed between both groups with respect to overall AE frequency (χ2 = 4.1, p = 0.04) and to discontinuation of standard oncological treatment (χ2 = 4.8, p = 0.03) with lower rates in the combinational group (20.1%, 35% respectively) compared to control (30.2%, 60.5%, respectively). Addition of VA to targeted therapy significantly reduced the probability of oncological treatment discontinuation by 70% (Odds ratio (OR) 0.30, p = 0.02). Conclusions: Our results indicate a highly significant reduction of AE-induced treatment discontinuation in all-stage cancer patients when treated with VA in addition to targeted therapy.