Background: Patients with differentiated thyroid cancer (DTC) are usually managed with total thyroidectomy and subsequent radioiodine ablation of the remnant thyroid tissue. L-thyroxine (L-T4) therapy (about 2 µg/kg) is required for life, with a wide variation in patient dose requirements. The iodothyronine deiodinase types I, II, and III (DIO1, DIO2, and DIO3, respectively) regulate the activity of the thyroid hormone via removal of specific iodine moieties from the precursor molecule T4. During LT4 replacement, the active hormone triiodothyronine (T3) levels strictly depend on DIO2-mediated activation of LT4. Therefore, the aims of this study were to investigate the association of DIO1 and DIO2 polymorphisms with DTC and L-T4 dose requirement in the Saudi population. Methods: A total of 1,067 (560 controls and 507 DTC thyroidectomized cases) Saudi Arabs were included. Serum free thyroxine and TSH levels were measured in the cases. We genotyped 1 DIO1 variant rs2294512_G and 3 DIO2 SNPs, rs1388378_T, rs12885300_T, rs225013_T, by TaqMan assay. Results: The DIO1 and DIO2 genotyping revealed an association between L-T4 dose requirement and rs1388378_T. Patients carrying the rs1388378_T allele required a lower l-T4 dose (145.91±33.31; P=.035). No significant association was found for these SNPs with cancer risk. Conclusions: Our study identified 1 DIO2 variant associated with L-T4 dose requirement. Thyroidectomized patients carrying T allele of rs1388378 need lower L-T4 dose to maintain normal TSH level thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.