Background: Adjuvant therapy decisions in breast cancer patients are based on accurate risk assessment. UPA/PAI-1 can be used for risk evaluation. Recently, the EndoPredict-clin score (EPclin), a second generation multigene test has been introduced into clinical practice. Aim of this prospective study is to compare risk assessment by uPA/PAI-1 and EPclin and to determine, how these parameters influence treatment decisions. Methods: 100 consecutive cases of ER-pos, HER2neg, intermediate risk breast cancer cases were enrolled in this study. EPclin and uPA/PAI-1 (for G2-tumors) were obtained by central pathology assessment of the patients´ surgical specimen. Type of adjuvant treatment was chosen after case discussion in an interdisciplinary tumor conference. Results: 94 Patients (pt) have been evaluated. Tumor grading within the presented cohort was as follows: G1: 15 pt (16%), G2: 66 pt (70%), G3: 13 pt (14%). 20 pt (21%) had positive axillary lymph node involvement. Tumor size was less than 1 cm in 27 pt (29%). EPclin could be assessed in 94 pt (100%). 32 pt (34%) were classified as “high risk” whereas 62 pt (66%) were classified as “low risk”. uPA/PAI was obtained from 54 pt (57%). 36 pt (67%) out of these 54 pt had high uPA/PAI-1 levels whereas 18 pt (33%) showed low uPA/PAI-1 levels. Only 2 pt (4%) with low uPA/PAI-1 levels were classified as “high risk” with EPclin, whereas 17 pt (32%) with high uPA/PAI-1 were classified as “low risk” via EPclin (p=0,003). In 29 cases (31%) treatment decision was influenced by EPclin: In 26 pt (28%) adjuvant chemotherapy (ctx) was omitted whereas in 3 pt (3%) ctx was added following the EPclin. Conclusions: This prospective study shows for the first time, that high risk status according to the EPclin score is strongly associated with a high risk status as defined by uPA/PAI-1. Providing analytically valid results for all patients evaluated EPclin’s clinical practicability was clearly superior to uPA/PAI-1. This finding, combined with the fact that EPclin assigns twice as many patients to the low risk group indicated that EPclin is a more versatile and powerful tool to help spare patients from chemotherapy than uPA/PAI-1.