This study assesses the homozygous and heterozygous status of sickle cell disease (SCD) and evaluates the relationship between consanguinity and the occurrence of HbS gene in families living in Marzouk region of Libya. The study revealed higher frequency (53.34%) of sickle cell trait (HbAS) in Marzouk region; whereas the prevalence of sickle cell anemia (HbSS) was nearly 10%. Out of 210 subjects, two cases of sickle cell with HbC (0.95%) were noticed. High frequency of consanguinity (72%) found in this study suggests that interrelation marriages are very common in Marzouk region and these are one of the major factors for high rate of sickle cell trait. In addition, large family size (average of 6-10 children/family) plays an important role in increasing the frequency of HbS. Surprisingly the carriers of HbAS showed some clinical complications of HbSS like jaundice and joints splenomegaly. Interestingly, one case of aplastic crisis was also detected in HbAS carriers. In the long run these findings will help in deciphering the mechanisms of the disease processes within SCD and management of the disease by implementing effective control measures and prevention strategies (like, genetic counseling, pre-marital screening etc.) along with care and rehabilitation of the affected population.