The exact cause of osteoporosis in patients with sickle cell disease (SCD) is not known, and various hypotheses have been put forward. To assess the effect of sex steroids on bone mass in SCD patients. In King Fahd Hospital of the university, Alkhobar, Saudi Arabia, a cross-sectional study was carried out. All patients known to suffer from SCD attending the hospital between August 2006 and August 2007 were subjects of the study. Blood was extracted for serum level of androgens, gonadotropins, thyroid stimulating hormone (TSH), calcium, phosphorus, and alkaline phosphatase. Measurement of bone mineral density (BMD) of hip and spine was done using dual-energy X-ray absorptiometry (DEXA). All tests were performed using SPSS (Statistical Package for Social Sciences), version 14.0, Chicago, Illinois, with P value of < 0.05 being statistically significant with confidence interval (CI) of 95%. One hundred three consecutive patients with an average age of 27.83 years were studied. Forty-five were males; and 58, females. Low bone mass (osteoporotic/osteopenic) was found in 62.2% of the patients in the male group and 67.06% in the female group. In males, testosterone level was not significant between different groups, but total estradiol levels were significantly lower in the osteopenic and osteoporotic patients (P < 0.003 and < 0.01 respectively). In female patients, estradiol and testosterone levels were lower in osteoporotic patients in comparison to non-osteoporotic patients (P = 0.05 and 0.001). Our study indicates that sex steroids play a major role in the development of osteopenia and osteoporosis in patients with SCD.