Background and Purpose: Experimental and clinical data suggest that overactivation of the sympathetic nerve system (SNS) is an essential mediator of stroke-induced immunodepression, which in turn increases susceptibility to post-stroke infections. In a post hoc analysis of the PANTHERIS (Preventive Antibacterial Treatment in Acute Stroke) trial, we investigated the impact of distinct lesion patterns on SNS activation, immunodepression, and frequency of post-stroke infections. Methods: Stroke volume, stress hormone levels, and immune function were determined on day 1 after stroke onset. Stroke localization was graded using the Alberta Stroke Programme Early CT score (ASPECTS). In univariate analysis, we investigated the impact of clinical (National Institutes of Health Stroke Scale, NIHSS) and imaging stroke characteristics (lesion volume, lateralization, localization grading) on autonomous nervous system activity (norepinephrine, cortisol), immune competence (monocytic HLA-DR expression), and the frequency of post-stroke infections. In a logistic regression model, we tested for independent factors that might increase susceptibility to post-stroke infections. Results: In a single-factor analysis, large stroke volume, lesions affecting distinct regions of the MCA cortex, and SNS activation (elevated norepinephrine levels) were associated with an impaired immune function (reduced mHLA-DR expression) and a higher susceptibility to post-stroke infections. Multivariate analysis identified increased levels of norepinephrine and infarction of the anterior MCA cortex as independent risk factors of post-stroke infections. Neither stroke severity nor stroke volume was independently associated with post-stroke infections. Conclusions: Apart from sympathetic activation, our data suggest that ischemic lesion in the anterior MCA cortex may be a major determinant of stroke-associated infection. This finding has to be confirmed in larger prospective studies.