The objective of the study was to detect changes of depression and cognitive level associated with right and left brain damage during SSRI treatment in subjects with post-stroke Major Depressive Disorder (MDD). After the baseline evaluation, the 45 patients included received a single oral dose of 20-40 mg of fluoxetine or 50-100 mg of sertraline. At day 0, 7, 14, 28, 42, and 56 a psychometric test battery comprising the Hamilton Depression Rating Scale (HDRS) and the Mini Mental State Examination (MMSE) was administered. In the whole group repeated measures ANOVAs revealed a highly significant (p < 0.0001) time effect for HDRS and MMSE scores. However, depression improved much more in right stroke subjects in comparison with left stroke subjects (p < 0.001 for the HDRS by laterality interaction). Moreover, there is a suggestion of a possible selective serotonin reuptake inhibitor (SSRI) efficacy in cognitive impairment associated to post-stroke MDD but in treatment-responders only. At the endpoint, chi-square analysis showed that there was a different prevalence rate of MDD between left (n = 10; 50 %) and right (n = 4; 16 %) stroke patients, whereas the prevalence rate of Minor Depression was identical (25 %). The SSRIs fluoxetine and sertraline could be efficacious treatments for post-stroke MDD but these findings suggest that left stroke could be a predictor of treatment resistance.