Background: Men diagnosed with prostate cancer frequently change their diet or lifestyle in an effort to decrease their risk of developing aggressive disease. Men managed with active surveillance (AS) may feel a greater need to modify risk factors because their cancer is untreated. However, no data on post-diagnosis diet and lifestyle factors from large prospective cohorts with long-term follow-up have been reported. We evaluated the influence of diet and lifestyle on the risk of prostate cancer biopsy progression in the largest prospective AS cohort in the US. Methods: Diet and lifestyle questionnaire completed by AS participants at enrollment. Progression determined by occurrence of Gleason score>7 or increase in tumor volume at annual surveillance biopsy. Analysis focused on 28 nutrients, 10 food groups, 9 supplements, 7 medication variables, and 2 lifestyle variables with a priori hypotheses. Data were analyzed by Wilcoxen test and logistic regression, with calorie adjustment by the residual method. Results: There were 723 men in the analysis, of whom 187 (26%) progressed. Median follow-up was 2.7 years. Men who progressed were significantly older, had higher PSA density, and higher biopsy tumor burden at diagnosis. In multivariable analyses, men who progressed had higher PSA density (OR=1.34 per 0.1 ng/ml/cc, p=0.017), were more likely to have >1 positive biopsy core (OR=2.9, p<0.0001), had higher percentage core involved with tumor (OR=1.04, p<0.0001), and were more likely to be current smokers (OR=4.1, p=0.004); duration of NSAID use and history of prostatitis approached significance. Conclusions: Cigarette smoking was significantly associated with risk of progression. This association must be viewed with caution due to the large number of variables tested. It is likely that many men considered to have progressed represent undersampling of the initial biopsy, rather than true biologic progression; this misclassification may obscure risk relationships. Ongoing analyses will be presented that explore whether associations differ for early vs late progression events. We believe this is the first report that smoking is associated with progression in men managed by AS.