Major depression is associated with cognitive deficits including memory, executive functions, and affect perception, which have been linked to dysfunction of fronto-subcortical networks. However, little is known about social cognition on more complex socially relevant tasks, such as humor processing. In this investigation a computerized humor-processing task was administered to 27 patients with a diagnosis of major depression (Dep) and 27 healthy controls (HC). Theory of mind (mentalizing) and executive functions were also assessed. Both groups were similar in IQ, age, and gender. Depressed patients performed below the control group with respect to both affective and cognitive aspects of humor processing, and these were related to mentalizing and executive performance. Our findings suggest social cognition deficits in major depression. Ability to process humor and appreciate mentalistic perspectives may in turn influence social interactions and should be given consideration in therapeutic approaches to depression.