Background: Vitamin B12 (Cobalamin) one of the most important vitamins for its normal functioning to maintain the nerve system and for their role in production of DNA. Objective: This study was aimed to measure and assess the serum Cobalamin levels in Sudanese patients with Sickle-cell disease (SCD) and compared with those without Sickle-cell disease. Materials and Method: This is a case control study conducted in Sudan during March 2015. A total of 160 volunteers were enrolled in this study. 80 were known Sudanese patients professionally diagnosed with homozygous sickle cell; their age ranged from 6 months to 15 years as patients group. Further 80 normal healthy were as control group; their age and gender were similar to patient group. Serum was prepared from clotted blood samples. The Cobalamin concentrations were measured in both groups of SCD patients and in a normal healthy control group using Enzyme Linked Immune immunosorbent assay method (ELISA), Map lap Plus-Italy. For statistical analysis, the laboratory parameters were compared between the two groups and tested for statistical significance using Statistical package for social scent (SPSS) version 20. Result: In this study the mean of serum Cobalamin in the sickle cell patients was statistically significantly lower compared with the normal non-sickle cell disease group with p value = 0.01. Conclusion: 7.1% of Sudanese sickle cell disease has a deficient serum Cobalamin (hypocobalaminemia).