Background: Radiation therapy or systemic chemotherapy with 3 cycles PEB represent the guideline recommended treatment options in marker negative clinical stage IIA/B seminoma. Despite a high cure rate of 90% to 94% and 82% to 90% in CS IIA and IIB, respectively, both therapeutic options are associated with significant long-term toxicities. It was the aim of our trial to evaluate the feasibility, oncological efficacy and treatment associated morbidity of primary nsRPLND in stage IIA/B seminoma. Methods: 30 patients with marker negative clinical stage IIA and IIB classical seminoma of the testis were recruited in the prospective trial. Primary goal was a relapse rate <20% within 2 years follow-up. Exclusion criteria were adjuvant carboplatin therapy for clinical stage I disease, extensive clinical stage IIb or clinical stage IIC disease, previous retroperitoneal surgery or radiation therapy, and positive tumor markers. All patients underwent nerve sparing RPLND with a modified template resection. None of the patients received adjuvant chemotherapy in the presence of positive lymph nodes. All patients underwent close follow-up with imaging studies and tumor markers at 3-month intervals during the first 2 years, at 6-month intervals in year 3 and annually thereafter. 10 pts had preoperative serum analysis of miR371. Results: Mean age was 34.2 (21-54) years. Mean follow-up is 29.4 (1-60) months and 32.5 (3-60) for those with a minimum follow-up of 3 months. All patients were treatment-naïve; 19 and 11 patients were diagnosed with stage IIA and IIB disease, respectively, at time of RPLND. 28 and 2 patients underwent open and robot assisted ns RPLND, respectively. Mean OR time was 131 (105-195) min, mean blood loss was < 150ml and the mean hospitalization time was 4.5 (3-9) days. We did not observe surgery associated complications > Clavien Dindo grade 3a. Mean number of dissected lymph nodes was 18 (7-57), the mean number of positive lymph nodes was 1.3 (1-2) and the mean diameter of positive nodes was 2.3 (0.8-4.1) cm. Histology of the resected lymph nodes revealed metastatic seminoma in 25 (80%) patients; 2 and 3 patients demonstrated embryonal carcinoma and benign disease, resp. 10 pts underwent serum analysis of miR371 preoperatively which predicted metastatic disease in 9/10 and benign histology in 1/1. 2/30 (6.7%) patients developed an outfield relapse 4 and 6 months postoperatively. Both patients were salvaged by systemic chemotherapy with 4 cycles PEB. Conclusions: NsRPLND results in a high cure rate at midterm follow-up and it is associated with a low frequency of treatment associated morbidities making this approach a feasible alternative to standard radiation therapy or systemic chemotherapy. MiR371p might be a useful marker to predict presence/absence of metastases in equivocal findings. Clinical trial information: DRKS00025384.