To evaluate lactation performance and changes in plasma and fecal lipopolysaccharide (LPS) concentrations in response to the supplementation of Saccharomyces cerevisiae fermentation product (SC), two dairy farms were selected. On each farm, 32 cows in early to mid lactation (21 to 140 DIM) were blocked by parity and days in milk (DIM), and randomly assigned to one of the two treatments within block (Control or 56 g SC/cow/d). Effect of SC on lactation performance (daily) and changes in blood and fecal LPS level were examined on d 0 and 28 of supplementation. The results showed that SC supplementation increased lactation performance of dairy cows on both farms. On Farm 1, milk production, 3.5% fat corrected milk (FCM), and yield of milk fat and protein were greater (p<0.01) for cows supplemented with SC. Supplementation of SC increased percentage milk fat (p = 0.029) from 81 to 110 DIM. There was no significant effect (p>0.05) of SC supplementation on percentage of milk protein, dry matter intake and feed efficiency. On Farm 2, cows supplemented with SC had a greater (p<0.05) milk yield, percentage of milk fat and milk protein, yield of milk fat and protein, 3.5% FCM and feed efficiency. Supplemental SC had no effect on LPS concentrations in feces (p>0.05) while it trended to reduce (p = 0.07 or 0.207) the concentration in plasma. The results indicate that supplemental SC can increase lactation performance of dairy cattle and has potential for reducing plasma LPS concentration.