Telemedicine applications are more and more used due to the rapid development of digital imaging and information and communication technologies. Medical information which include digital medical images and patient’s information are extracted and transmitted over insecure networks for clinical diagnosis and treatments. Digital watermarking is one of the main approaches used to ensure the security of medical images. Nevertheless, in some cases, the only use of digital watermarking is not sufficient to reach a high level of security. Indeed, the watermark could carry essential patient information and needs to be protected. In such cases, cryptography may be used to protect the watermark and to improve the overall secured management in the medical environment. In this paper, we propose a clone-resistant watermarking approach combining a difference expansion watermarking technique with a cryptographic technique based on secret keys generated by a clone-resistant device called Secret Unknown Ciphers (SUCs). The use of SUCs to sign the watermark enforces the security of medical images during their transfer and storage. Experimental results show that the system provides a high level of security against various forms of attacks.