Retrograde drilling of osteochondral lesions has obtained acceptable results in the initial stage. Intraoperatively not all lesions are accessible with the arthroscopic technique, despite being readily identifiable with modern imaging preoperatively. As an alternative, open surgical treatment is recommended to achieve good results. The use of computer-assisted navigated retrograde drilling of osteochondral lesions has been described with promising results as a new technique. Computed tomography (CT)- and fluoroscopy-based navigation systems in current use are limited in their flexibility. The drawbacks of fluoroscopy are lack of three-dimensional imaging intraoperatively. CT-based navigation still requires intraoperative cumbersome registration, extra preoperative planning, and imaging with further technical resources. In the current case report, we describe a patient with an osteochondral lesion of the posteromedial talus. In addition to the current method of arthroscopic evaluation and treatment, we also introduce an alternative technique of using Iso-C(3D)-based navigation-assisted retrograde drilling of the lesion. The advantages of this technique are an actual intraoperative three-dimensional imaging for the use of navigation without the need for anatomical registration and an immediate postoperative control of surgical treatment. The results of this case report demonstrate accurately navigated drilling with the described system. The accuracy was confirmed with immediate intraoperative Iso-C(3D) and postoperative CT scans. Our results indicate that the use of an Iso-C(3D) navigation system is a possible alternative to arthroscopic or open drilling for osteochondral lesions of the talus. To provide further evidence for the use of Iso-C (3D)-based drilling, current studies will start at our institution.