Chronic hemolysis, with consequent hyperbilirubinemia, predisposes SS patients to pigment gallstones. The other factors which influence the development of stones in these patients have not been identified. We have carried out a combined prospective and retrospective study of SS patients in Kuwait and specifically investigated the influence of coexistent α-thal trait on the prevalence of gallstones. A total of 45 patients (30 males, 15 females) with ages ranging from 1 to 16 years (mean 7.2 ± 3.1) were studied. Most were either homozygotes for the Saudi Arabia/India haplotype (86.7%) or compound heterozygotes for this and the Benin haplotype (11.1%). They were screened for gallstones with ultrasonography. α-Globin genotypes were determined using a combination of PCR and allele-specific oligonucleotide hybridization techniques to identify the common α-thalassemia alleles in this population. Gallstones were detected in 7 (15.6%) patients (4 males, 3 females), whose mean age (10.5 ± 5.5 years) was significantly higher than that (6.8 ± 3.2 years) of those without stones (p < 0.01). The mean total Hb of the former (8.4 ± 0.8 g/dl) was also significantly (p < 0.05) lower than in the latter (9.5 ± 1.3 g/dl), while the difference in mean Hb F levels was not significant. None of the 4 α-thal homozygotes had gallstones while 2 of 13 heterozygotes and 5 of the 23 patients without coexistent α-thal had. The differences in these proportions are statistically significant (χ2 = 20.4, p < 0.001). It therefore appears that coexistent α-thal decreases the chance of developing gallstones in Arab SS patients. This may be related to less hemolysis in such patients as shown by their higher mean Hb level.