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Weaning imposes multiple stressors that reduce feed intake and impair intestinal integrity. Furthermore, poor environmental management could compound the high stress period increasing morbidity and mortality of postweaning piglets. The objective of this research was to investigate the effect of supplemental Saccharomyces cerevisiae on postweaning growth performance, fecal scores and immune parameters in a clean or dirty nursery environment. The experiment was a 2 X 2 factorial design with two dietary treatments fed in a sanitized (following barn SOP) and unsanitized (pits flushed, feeders and pens scraped) nursery environment. Weaned piglets (n=260 and 5pigs/pen; 20.8 day of age) were allotted to the following dietary treatments: 1) control or 2) Saccharomyces cerevisiae (0.1% in phase 1 and 2 and 0.05% phase 3 diets) for 5-wks postweaning. On days 3, 7, 14, 21 and 35 fecal scores/pen and blood samples were collected for monitoring diarrhea and measurement of cytokines. Overall, pigs fed Saccharomyces cerevisiae had greater ADG compared to control fed pigs regardless of environment (P= 0.09; 379 vs. 357 g/d, Saccharomyces cerevisiae vs control, respectively), and final pen weights at d35 were greater in Saccharomyces cerevisiae vs. control fed pigs (101 vs. 97 kg/pen; P < 0.05). Pigs reared in the dirty environment vs the clean environment had reduced overall ADG (352 vs 384 g/d, respectively; P = 0.01), and pigs raised in the dirty environment had an overall greater F:G ratio compared to pigs raised in clean environments; 1.87 vs. 1.76 g/g (P = 0.09). Diarrhea scores were increased in the dirty environment compared to the clean environment on days 3 and 7 (P < 0.01). Serum tumor necrosis factor alpha (TNF-α) concentrations were not significantly affected by diet or environment. In conclusion, Saccharomyces cerevisiae increased overall ADG in weaned pigs regardless of environment and environmental challenge reduced growth and efficiency parameters in the nursery pigs.