Previous in vitro studies demonstrated that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a negative regulator of EGFR, is a novel agent for suppressing bladder cancer. However, the role that LRIG1 plays in bladder cancer growth in vivo has not been elucidated in animal or clinical studies. Thus, to evaluate the suppressive effects of LRIG1 on human invasive bladder cancer in vivo, we transferred LRIG1 into athymic mice bearing T24 invasive bladder cancer xenografts mediated by an adenoviral vector. Correlations between LRIG1 expression and tumorigenicity, EGFR expression, xenograft proliferation and angiogenesis were assessed, respectively. The results indicated that tumor volume growth was retarded via Ad-LRIG1 intratumoral injection. In addition LRIG1 upregulation was well correlated with a reduction in EGFR expression and the proliferation rate of xenografts. Furthermore, microvessel densities were reduced and correlated with Ad-LRIG1 administration. No significant macroscopic and microscopic pathological abnormality was observed in the liver, kidney and lungs of Ad-LRIG1-administered mice. This new insight provides evidence that downregulation of EGFR expression by LRIG1 may comprise a potential novel and safe therapeutic approach for improving the prognosis of invasive bladder cancer.