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To characterize CD4+CD28null cells in chronic hyperuricemia and investigate whether allopurinol could restore CD28 expression and the balance of T helper phenotypes. Asymptomatic individuals with chronic hyperuricemia and ultrasonographic findings evocative of urate deposition in the joints. Age- and gender-matched normouricemic individuals were also studied. Oral allopurinol at 150 mg/day for 4 weeks, followed by 300 mg/day through week 12. Color-flow cytometry on peripheral blood mononuclear cells (PBMC) with antibodies against CD4, CD28, T-bet (Th1), GATA-3 (Th2), and RORγt (Th17). Six patients (five men, median age of 53 years) and seven controls were studied. At baseline, hyperuricemic patients had more CD4+CD28null/CD4+ cells than normouricemic subjects (36.8% vs. 6.1%; p = 0.001), with a predominance of T-bet+ cells (98.5% vs. 6.6%; p = 0.001) and few RORγt+ cells (0.7% vs. 89.4%; p = 0.014). In hyperuricemic patients, the number of CD4+ cells/10,000 PBMC was similar before and after allopurinol (3378 vs. 3954; p = 0.843). Conversely, CD4+CD28null cells decreased from 36.8% (23.0–43.7) to 15.8% (4.7–28.1; p = 0.031). CD4+CD28nullT-bet+ cells decreased from 98.5% (95.0–99.4) to 88.3% (75.2–98.9; p = 0.062), CD4+CD28nullGATA-3+ cells increased from 0% (0–4.0) to 2.8% (0.1–15.6; p = 0.156), and CD4+CD28nullRORγt+ cells increased from 0.7% (0.4–7.0) to 4.5% (1.3–28.1; p = 0.031). The CD4+CD28null cell subset is abnormally expanded in chronic hyperuricemia, despite the absence of overt urate-related disease. Allopurinol may partially restore CD28 expression on CD4+ cells while enhancing the homeostatic balance of T helper phenotypes. ClinicalTrials.gov, number NCT04012294. Key Points • Chronic hyperuricemia is characterized by an abnormal expansion of senescent CD4+CD28null cells, which are aberrantly polarized toward a Th1 effector phenotype. • Allopurinol administration restores CD28 expression on CD4+cells while enhancing the homeostatic balance of helper T phenotypes. [ABSTRACT FROM AUTHOR]