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Clinical staging in patients with muscle invasive bladder cancer misses up to 25% of lymph node metastasis. These patients are at high risk for disease recurrence and improved clinical staging is critical to guide management.Whole transcriptome expression profiles were generated in 199 patients who underwent radical cystectomy and extended pelvic lymph node dissection. The cohort was divided randomly into a discovery set of 133 patients and a validation set of 66. In the discovery set features were identified and modeled in a KNN51 (K-nearest neighbor classifier 51) to predict pathological lymph node metastases. Two previously described bladder cancer gene signatures, including RF15 (15-gene cancer recurrence signature) and LN20 (20-gene lymph node signature), were also modeled in the discovery set for comparison. The AUC and the OR were used to compare the performance of these signatures.In the validation set KNN51 achieved an AUC of 0.82 (range 0.71–0.93) to predict lymph node positive cases. It significantly outperformed RF15 and LN20, which had an AUC of 0.62 (range 0.47–0.76) and 0.46 (range 0.32–0.60), respectively. Only KNN51 showed significant odds of predicting LN metastasis with an OR of 2.65 (range 1.68–4.67) for every 10% increase in score (p <0.001). RF15 and LN20 had a nonsignificant OR of 1.21 (range 0.97–1.54) and 1.39 (range 0.52–3.77), respectively.The new KNN51 signature was superior to previously described gene signatures for predicting lymph node metastasis. If validated prospectively in transurethral resection of bladder tumor samples, KNN51 could be used to guide patients at high risk to early multimodal therapy.