OBJECTIVE To examine whether serum cholesterol in early middle age is associated with age-related macular degeneration (AMD) later in life. METHODS A group of Helsinki Businessmen Study (HBS) participants (n = 209) were recruited for the study. Total cholesterol (TC), triglyceride and body mass index (BMI) were measured at the HBS baseline visit in 1964-1973. Lipid subfractions, BMI, smoking status and statin use were recorded in 2011 and fundus photographs graded for AMD in 2005-2012. The subjects were genotyped for the main AMD risk single nucleotide polymorphisms (SNPs). RESULTS TC measured at baseline 1964-1973 was significantly higher in subjects later developing intermediate or late AMD (6.67 mmol/l versus 6.20 mmol/l, p = 0.024) or with drusen size of ≥125 µm (6.68 mmol/l versus 6.21 mmol/l, p = 0.030) compared with the rest of the study population. TC, LDL and TG values at follow-up 2011 were lower in subjects with AMD compared to those without, whereas HDL levels showed no difference. In multivariate analysis, baseline TC associated with intermediate or late AMD (OR 1.59, p = 0.004) and drusen size ≥ 125 µm (OR 1.57, p = 0.006) when corrected for age, BMI, AMD risk SNPs and smoking. Lipid values measured 2011 had no associations after correction. CONCLUSIONS High systemic total cholesterol in early middle age may have a role in the initial development of AMD, especially in patients later developing large drusen.