Introduction Associations between cholesterol and prostate cancer have been inconsistent and limited to a small number of studies with significant methodological limitations.

Methods We conducted a prospective cohort study of 12 933 men who were enrolled in two of the Midspan studies (took place in Scotland) between 1970 and 1976 with follow-up to 31 December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence.

Results 676 men developed prostate cancer in up to 37 years follow-up. We found no association between cholesterol level and overall risk of prostate cancer incidence. However, cholesterol was positively associated with hazard of high grade (Gleason score ≥8) prostate cancer incidence (p<0.05). The association was greatest among men in the 4^th highest quintile for cholesterol, 6.1–<6.69 mmol/l (HR 2.30, 95% CI 1.27 to 4.10) compared with the baseline of <5.05 mmol/l. Exclusion of incident cancers up to 5 years after baseline cholesterol assay did not significantly affect the observed associations.

Conclusions Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but no overall association between cholesterol and prostate cancer risk was found. Further research is needed to determine the underlying biological mechanisms for the association.