Background/Aims: Is cholecalciferol (D3) superior to ergocalciferol (D2) in treating nutritional vitamin D deficiency in chronic kidney disease (CKD)? The answer to this question has not been fully explored. Methods: A retrospective analysis of 57 patients with non-dialysis-requiring CKD was conducted to assess the relative effectiveness of D2 versus D3 replacement on circulating 25(OH)D levels. Levels of 25(OH) D were assessed at baseline, after attempted repletion with D2, and then after attempted repletion with D3. The relative paired differences of the drug treatment effects were tested using t-tests. Multiple regression modeling was used to determine the factors significantly associated with differential responsiveness to the drugs. Results: The mean (SEM) age was 66.4 ± 1.4 and mean eGFR was 40.5 ± 2.2 ml/min/1.73 m2. The baseline 25(OH)D level was 15.3 ± 0.8 ng/ml. After standardizing to 100,000 units of drug, increases after cholecalciferol (2.7 ± 0.3 ng/ml) were more than twice as great as those from ergocalciferol (1.1 ± 0.3 ng/ml) (p < 0.0001). A sensitivity analysis, which pooled the results of an additional 109 individuals treated with ergocalciferol alone, revealed similar findings (standardized change 2.7 ± 0.3 vs. 1.6 ± 0.3 ng/ml, p = 0.0025). Factors associated with a superior response to cholecalciferol were lower baseline 25(OH) D level at the start of therapy (p = 0.015) and the interaction of sex and age (p = 0.0048), with younger females tending to benefit relatively more from cholecalciferol than older males did. Conclusion: Cholecalciferol may be superior to ergocalciferol in treating nutritional vitamin D deficiency in non-dialysis CKD.