Background and Purpose The aim of the present study was to evaluate the relation between poststroke depression and lesion location, avoiding previous methodological shortcomings. In particular, we intended to determine whether patients with left frontal lesions showed the highest depression scores. Methods Patients in the study, categorized on the basis of lesion location, included 149 stroke patients with lesions located in the anterior, central, or posterior regions of the right or left hemisphere. Verbal and nonverbal mood measures as well as the Hamilton Depression Scale Overall Score were the dependent measures of our investigation. Furthermore, the number of patients who could not be assessed or could be evaluated only with the nonverbal mood measure due to the presence of severe language disorders was recorded. Results No significant relation was observed between depressed mood and lesion location. Approximately one quarter of the left brain–damaged patients were partially or totally excluded from the study because of severe language disorders. Conclusions Our data appeared to show that when methodological pitfalls and selection bias are carefully controlled, left frontal lesions are not a major determinant of poststroke depression.