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Bladder cancer is one of the more common malignancies in humans and the most expensive tumor for treating in the Unites States (US) and Europe due to the need for lifelong surveillance. Non-invasive tests approved by the FDA have not been widely adopted in routine diagnosis so far. Therefore, we aimed to characterize the two putative tumor suppressor genes <i>ECRG4</i> and <i>ITIH5</i> as novel urinary DNA methylation biomarkers that are suitable for non-invasive detection of bladder cancer. While assessing the analytical performance, a spiking experiment was performed by determining the limit of RT112 tumor cell detection (range: 100&#8722;10,000 cells) in the urine of healthy donors in dependency of the processing protocols of the RWTH cBMB. Clinically, urine sediments of 474 patients were analyzed by using quantitative methylation-specific PCR (qMSP) and Methylation Sensitive Restriction Enzyme (MSRE) qPCR techniques. Overall, <i>ECRG4</i>-<i>ITIH5</i> showed a sensitivity of 64% to 70% with a specificity ranging between 80% and 92%, i.e., discriminating healthy, benign lesions, and/or inflammatory diseases from bladder tumors. When comparing single biomarkers, <i>ECRG4</i> achieved a sensitivity of 73%, which was increased by combination with the known biomarker candidate <i>NID2</i> up to 76% at a specificity of 97%. Hence, <i>ITIH5</i> and, in particular, <i>ECRG4</i> might be promising candidates for further optimizing current bladder cancer biomarker panels and platforms.