Objectives: This study investigates serum immunoglobulin fractions (IgG, IgA and IgM) and IgG subclasses (IgGScs; IgG1–4) in SS patients with the Saudi Arabia/India (SAI) haplotype. The influence of gender, Hb F levels, spleen function and coexistent α-thal trait were studied. Methods: Immunoglobulins and IgGScs were assayed using nephelometry. βs-globin gene cluster haplotyping and α-globin genotyping were done using a combination of PCR and allele-specific oligonucleotide hybridization techniques. Results: Twenty-nine steady-state (i.e. not acutely ill) SS patients (23 SAI homozygotes and 6 SAI/Benin compound heterozygotes) and 34 healthy age- and sex-matched Hb AA and AS controls were studied. Mean serum IgG and IgA values were significantly higher in the patient group, while there were no significant differences in the mean IgGScs. The patient group was further subdivided depending on whether the spleen was normally visualized (group 1), partially visualized (group 2) or not visualized (group 3) on 99mTc-labeled tin colloid scintigraphy. There was a significant sequential increase in mean IgG values from group 1 to group 3 but the reverse was true for IgM, while IgA showed no consistent trend. The mean levels of IgG1 and IgG3 were significantly higher in group 3 (p < 0.01). Hb F level did not influence immunoglobulins or IgGScs, but SS patients with coexistent α-thal trait tended to have lower IgG and IgG1 levels. Conclusions: Increased serum IgG is associated with poor splenic function and recurrent infections among SAI patients, while increased IgM is seen mainly in those with relatively normal splenic function.