There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Lipopolysaccharide (LPS) infusion is a well established experimental model used to investigate host systemic inflammatory responses. It was hypothesized that LPS challenge, by virtue of its provoked host inflammatory response, might increase the propensity to the development of new-onset AF. A post hoc analysis was performed of prospective data collected for 652 healthy men (mean age 27+/-5 years, all without history of AF) who were challenged with LPS according to a standard experimental protocol. All subjects underwent a detailed health screening before inclusion. After LPS challenge, all subjects underwent continuous cardiac monitoring for a minimum of 8 hours and were reviewed again using rhythm assessments at 24 hours and after 7+/-3 days. Effects of LPS on high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and neutrophil counts as indexes of an inflammatory response were also assessed. LPS led to overall marked increases in high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and neutrophil counts (all p<0.0001) and an average temperature increase of 1.1 degrees C. There was no evidence of new-onset AF in the subjects challenged. In conclusion, experimental LPS challenge led to a significant increase in acute inflammatory indexes, but did not increase the propensity to new-onset AF in a young low-risk population.