Context: Whether ergocalciferol (D-2) and cholecalciferol (D-3) are equally effective to increase and maintain serum 25-hydroxyvitamin D [25(OH)D] concentration is controversial. Objective: The aim of the study was to evaluate the effect of daily and once monthly dosing of D-2 or D-3 on circulating 25(OH) D and serum and urinary calcium. Design, Setting and Participants: In a university clinical research setting, 64 community dwelling adults age 65+ were randomly assigned to receive daily (1,600 IU) or once-monthly (50,000 IU) D-2 or D-3 for 1 yr. Main Outcome Measures: Serum 25(OH) D, serum calcium, and 24-h urinary calcium were measured at months 0, 1, 2, 3, 6, 9, and 12. Serum PTH, bone-specific alkaline phosphatase, and N-telopeptide were measured at months 0, 3, 6, and 12. Results: Serum 25(OH) D was less than 30 ng/ml in 40% of subjects at baseline; after 12 months of vitamin D dosing, levels in 19% of subjects (n = 12, seven receiving daily doses and five monthly doses) remained low, despite compliance of more than 91%. D-2 dosing increased 25(OH) D-2 but produced a decline (P < 0.0001) in 25(OH) D-3. Substantial between-individual variation in 25(OH) D response was observed for both D-2 and D-3. The highest 25(OH) D observed was 72.5 ng/ml. Vitamin D administration did not alter serum calcium, PTH, bone-specific alkaline phosphatase, N-telopeptide, or 24-h urine calcium. Conclusions: Overall, D-3 is slightly, but significantly, more effective than D-2 to increase serum 25(OH) D. One year of D-2 or D-3 dosing (1,600 IU daily or 50,000 IU monthly) does not produce toxicity, and 25(OH) D levels of less than 30 ng/ml persist in approximately 20% of individuals. Substantial between-individual response to administered vitamin D-2 or D-3 is observed. (J Clin Endocrinol Metab 96: 981-988, 2011)