Background: Biochemical parameters vary in subjects with different hemoglobin phenotypes, compared with normal controls. Aim: The aim was to evaluate serum creatine kinase (CK) activity and inorganic phosphate concentrations in Nigerian adults with homozygous and heterozygous hemoglobin phenotypes. Subjects and Methods: A prospective study, carried out at the hematology out‑patient clinic of our hospital, a community health center and a private hospital, all in Anambra state. Subjects included hemoglobin phenotypes AA, AS, and SS, in steady state and vaso‑occlusive crisis (VOC). Samples were collected for serum CK activity and inorganic phosphate concentrations. Data obtained were analyzed using SPSS 16.0 (SPSS Inc., Chicago IL, USA). Means were compared using the Student’s t‑test and statistical significance was set at P < 0.05. Results: A total of 100 subjects participated in the study. There was a statistically significant difference in the means of serum CK activity in hemoglobin SS (HbSS) in VOC versus hemoglobin AA (HbAA) (P = 0.01) and HbSS in steady state versus HbAA (P = 0.02) but not in hemoglobin AS (HbAS) versus HbAA (P = 0.79) and HbSS in VOC versus HbSS in steady state (P = 0.06). A statistically significant difference was noted in the means of serum inorganic phosphate concentration in HbSS in VOC versus HbAA (P = 0.01), but not in HbSS in steady state versus HbAA (P = 0.43), HbSS in VOC versus HbSS in steady state (P = 0.09) and HbAS versus HbAA (P = 0.20). Conclusion: Sickle cell disease is a predictor for high serum CK activity and low serum concentration of inorganic phosphate, particularly in VOC. There may be a need to monitor serum CK activity in HbSS subjects presenting with major VOC.