Interacting with computer-generated 3-dimensional (3D) data can pose challenges in the control of 3D objects and navigation in 3D space. The traditional mouse-driven interfaces are limited to controlling two degrees of freedom (DOF) at a time. The current research examines the efficacy of a two-handed interface (THI), "iMedic," that uses two 6-DOF controllers that afford a more direct style of manipulation of 3D medical imagery. The iMedic interface employs a 3D "multi-touch" type of interaction for manipulation of objects, and self-navigation in space. Medical 3D images of human anatomy from computer tomography (CT) scans were used as a testbed in comparing the two interface: the THI, and a traditional keyboard-and-mouse interface (KMI) commonly used in medical imaging contexts. Novice system users with medical background used each system to carry out navigation, visual search, and measurement tasks with abstract synthetic and realistic anatomical objects. Results indicate that for novice users, there was no clear advantage to either interface in subjective or objective measures. However, a case study of an experienced user showed clear advantages in all tasks using the THI. Reasons for the findings are examined, and interface design implications are discussed.