Abstract Patient-derived xenografts (PDX) passaged in immunocompromised mice are a well-established system for preclinical efficacy testing of anti-cancer agents. Typically, PDXs are pre-screened either in vitro or via molecular analysis, and selected models are then tested in groups of 8 to 12 mice to confirm or evaluate the efficacy of a treatment relative to a vehicle control group. This approach results in highly reliable and reproducible efficacy data. However, it is often desirable to test large panels of tumor models in vivo in order to properly take genetic diversity into account. Such experiments can be cost-prohibitive in conventional study layouts, which results in fewer models being tested. The Single Mouse Trial (SMT) format addresses the need for compound testing in larger, more diverse tumor populations. This format employs a single mouse per PDX model and treatment arm, thereby enabling the investigation of efficacy in substantially larger panels of PDX models. In order to better mirror inter-patient response diversity observed in the clinic, less emphasis is put on the statistical robustness of response data for individual models. In the study presented here, six SoC drugs were tested in the SMT format in colorectal (cetuximab, oxaliplatin, irinotecan, 5-FU) and non-small-cell lung cancer (cetuximab, paclitaxel) PDXs, and results were compared to those obtained from standard format experiments with 5 - 10 mice per group. Dosing and schedules were adapted to clinical standards. Data for 19 CXF and 16 NSCLC models showed that in 77% of the cases, results obtained from the single mouse trial format were in line with results from standard efficacy tests. Furthermore, in 10% of the cases, efficacy was similar by trend between the two formats. Notable discrepancies were seen mainly in tumors exhibiting intermediate sensitivity. Our findings indicate that for the drugs tested here, the risk of misjudging the efficacy in a given PDX model based on SMT is low. This risk could be further lowered by increasing group sizes to 3 mice. For the identification of biomarkers which requires accurate efficacy data, such an intermediate format between the SMT and the standard format might be advantageous. Citation Format: Christina Gredy, Julia B. Schüler, Nina Zanella, Heinz-Herbert Fiebig, Thomas Metz. Single mouse trials, a concept using patient-derived tumor xenografts for large scale in vivo screens. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2890. doi:10.1158/1538-7445.AM2015-2890