The aim of the present study was to investigate the relationships between post-stroke depression (PSD), lesion location and cognitive deficits after stroke. We studied 20 patients within the first month after clinical onset (T1), and one year later (T2). PSD was observed in 55% of patients at T1 and 35% of patients at T2. At T1, depression was reliably correlated with dorsal lesions in the right-hemisphere and anterior lesions in the left hemisphere. Lesion location was no longer a significant factor determining PSD at T2. Changes in PSD, from T1 to T2, were inversely correlated with the performances in cognitive tests exploring the domains of attention, visuospatial learning, executive/motor functions, and with the global composite cognitive score. Our data suggest that: 1) in the mix of influences that may produce PSD, lesion location is the main factor determining mood changes after stroke in the first month; 2) PSD produces deficits in attention, learning, and executive/motor functions, without affecting language and other cognitive domains.