Background: Recurrence rates in intermediate risk non-muscle invasive bladder cancer (NMIBC) are high and therefore, clinical guidelines recommend adjuvant instillations. However, the exact regimen with an exact number of instillations and the chemotherapeutic agent to be used are not clearly defined. During the last years we have established a standardized pipeline to generate patient-derived organoids (PDO) from cold cup biopsies of NMIBC. We showed that the subsequent organoids maintain key features of the parental tumor and share the molecular landscape. Moreover, our pipeline allows to investigate drug response to different agents in a standardized manner. Methods: In this ongoing, open-label, single center phase II trial, we aim to use drug screens in PDO of patients with intermediate risk NMIBC to guide drug selection for intravesical instillation. Patients with diagnosis of intermediate-risk NMIBC are enrolled. PDO are generated from biopsies prior transurethral resection of the bladder tumor. On the generated PDO drug response is determined to four chemotherapeutic agents that have already been used for bladder instillations in the literature (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). The most effective drug is selected for adjuvant instillation into the bladder once weekly for 6 instillations. The follow-up thereafter is performed according to European guidelines. The primary endpoint of the study is to determine the proportion of patients for which a specific selection of chemotherapeutic agent for intravesical instillation can be determined by using drug screens in PDOs. Secondary endpoints are recurrence- and, progression free survival, quality of life and translational studies. The null hypothesis, that a drug prediction will only be possible in 65% of patients, will be tested against a one-sided alternative. Assuming that the real proportion is 85%, 31 participants should show a statistically significant result at 5% significance and 80% power (exact binomial test). Due to early termination of 10%, a total number of 34 patients will be included. We are successfully conducting a trial to implement drug screens in PDO into daily routine and to guide patient treatment. This is a novel concept to precise treatment selection in patients with intermediate-risk NMIBC. When the primary endpoint is met, a modification of the trial with larger sample size, novel compounds and a focus oncological outcomes is foreseen. Clinical trial information: NCT05024734.