Inhibiting gene expression in specific tissues and organs through intravenous injection would be the ultimately preferred method of disease therapy. Here, we report the successful delivery of lentivirus-mediated small interfering RNA (siRNA) to suppress GFP gene expression in living mice. First, a lentiviral vector with siRNA (len-siRNA) driven by H1 promoter was constructed to effectively suppress GFP expression in Mel cells. When the len-siRNA virus was injected into transgenic mice, the GFP expression was significantly suppressed (over 15% reduction) in the recipient mice compared to the control mice and the suppressing effect lasted more than 1 week after injection. Our results demonstrate a new effective approach to inhibit gene expression by siRNA and lentiviral vectors. Further development of this drug for suppression of gene expression siRNA should result in applications not only for cancers but also for infectious and immune diseases.