Serious games are games in which the main goal is not entertainment, but a serious purpose ranging from the acquisition of knowledge to interactive training, to name just a few. These games are emerging as a promising educational technique across various domains (such as the military, education, politics, management, and engineering) and are attracting growing attention in healthcare thanks to the possibility of: increasing the level of interactivity of the application and the motivation of the user, allowing adaptation to the user’s level of competence, flexibility over time, repeatability, and continuous feedback.

In recent years, there has been a growing interest in applying virtual reality (VR) techniques to the development of serious games for creating immersive experiences. VR and augmented reality (AR) have a long history in the healthcare sector, offering the opportunity to develop a wide range of tools and applications aiming at improving the quality of care and efficiency of services for professionals and patients alike.

The best-known examples of VR/AR applications in the healthcare domain include surgical planning and medical training by means of simulation technologies. The techniques used in surgical simulation have also been applied to cognitive and motor rehabilitation, pain management, and patient and professional education.

Recently, healthcare has also become one of the biggest adopters of mixed reality (MR), which merges real and VR content to generate new environments where physical and digital objects not only co-exist but are also capable of interacting with each other in real time. MR encompasses both VR and AR applications.

These novel applications are attracting growing attention from users and researchers, but many cognitive and perceptual issues still need to be completely understood and resolved to fully take advantage of the disruptive potential of these emerging technologies in healthcare, and to minimize side effects of VR/AR technologies such as “cybersickness”. Moreover, efforts should be made to strengthen the experience of “presence”, the level of acceptance, and the compatibility of MR technology with the general population (including the elderly and sick people).

In light of the above, this Special Issue was introduced to gather and publish original scientific contributions that explore opportunities and address the challenges of serious games, VR/AR, and MR applications in healthcare. There were 11 papers submitted to this Special Issue, and 8 papers were accepted.