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Purpose: CD44v6 is a cell surface protein involved in cell migration, cell adhesion, tumor progression and metastatic spread. We evaluated its role as a molecular marker for urothelial bladder cancer. Materials and Methods: A tissue microarray was constructed containing 410 primary urothelial bladder cancers, each in triplicate. Immunohistochemical staining was done with a commercially available antibody. The percent of tumor cells staining positive for CD44v6 was evaluated and we assessed associations with stage, grade and survival. Results: CD44v6 expression was higher in noninvasive (Ta, Tis) vs invasive (T1–T4) tumors (p <0.001). It decreased with increasing grade (p <0.001). In patients who underwent transurethral bladder resection absent CD44v6 expression was associated with a 2.3-fold increased risk of recurrence (95% CI 1.28 to 4.08). Median time to recurrence for tumors with vs without CD44v6 expression was 23 vs 9 months (p = 0.003). In a multivariate Cox model absent CD44 expression was an independent adverse prognostic factor for tumor recurrence (HR 2.33, p = 0.006). In cystectomy cases median overall survival for CD44v6 nonexpression vs expression was 30 vs 75 months (p = 0.0027) and CD44v6 expression was retained as an independent prognostic factor for overall survival (HR 1.54, p = 0.042). Conclusions: Absent CD44v6 expression is an independent adverse predictor of urothelial bladder cancer recurrence and overall survival. Routine evaluation of CD44v6 expression may allow the identification of high risk patients who require more intensive surveillance or aggressive therapy. Targeting of CD44v6 with monoclonal antibodies may provide new avenues for urothelial bladder cancer imaging and treatment. [Copyright &y& Elsevier]