Background/Aims: High atrial natriuretic peptide (ANP) serum levels are seen in acute renal failure (ARF) due to impaired ANP clearance, but the response of ANP to blood volume expansion is blunted. ARF-associated hypothyroidism influences ANP clearance but it may also play a role in the synthesis and release of ANP because in primary hypothyroidism both mechanisms are disturbed. The aim of this study is to analyze whether thyroxin (T<sub>4</sub>) supplementation improves the synthesis and release of ANP in ARF. Methods: Four groups of rats were studied: group C (control); group ARF; Group ARF-T<sub>4</sub> (ARF supplemented with T<sub>4</sub>), and group Tx (thyroidectomized). Serum creatinine (SCr), creatinine clearance (CrCl), total T<sub>4</sub>, total triiodothyronin (T<sub>3</sub>), plasma ANP, ANP response to acute saline load and atrial content of mRNA-ANP were measured 5 days after ARF induction with potassium dichromate. Results: CrCl was 1.8 ± 0.4 ml/min in group C, and it significantly dropped to 0.6 ± 0.5 in ARF (p < 0.01), T<sub>4</sub> improved it (1.7 ± 0.7 in ARF-T<sub>4</sub>, p < 0.01) and Tx did not change it. Plasma ANP was higher in ARF as compared with C (152 ± 23 vs. 52 ± 21 fmol/l, p < 0.01). In ARF-T<sub>4</sub>, ANP was higher than in C but lower than in ARF (85 ± 28 fmol/l, p < 0.01). No changes were observed in Tx rats (48 ± 17 fmol/l). The atrial content of mRNA-ANP was 0.06 ± 0.025 mRNA-ANP/mRNA-β-actin ratio units in group C, it was higher in ARF (0.13 ± 0.025, p < 0.01) and lower in Tx (0.04 ± 0.01, p < 0.05) as compared to C. Supplementation with T<sub>4</sub> increased the mRNA-ANF content (0.18 ± 0.2 mRNA-ANP/mRNA-β-actin ratio units, p < 0.05) over ARF. Plasma ANP response to saline load was 45 ± 7% in C, but it was reduced in ARF and Tx (20 ± 10 and 26 ± 10%, p < 0.01). In ARF-T<sub>4</sub> the response was restored (36 ± 9%, p < 0.01 vs. ARF). Conclusion: Thyroid hormones modulate the synthesis and release of ANP in ARF. Although the effect is probably direct, T<sub>4</sub>-induced amelioration of renal damage may also play a significant role by improving the uremic milieu.