Sarcolipin (SLN), a key regulator of cardiac sarco(endo)plasmic reticulum (SR) Ca²⁺ ATPase, is predominantly expressed in atria and mediates β-adrenergic responses. Studies have shown that SLN mRNA expression is decreased in human chronic atrial fibrillation (AF) and in aortic banded mouse atria; however, SLN protein expression in human atrial pathology and its role in atrial SR Ca²⁺ uptake are not yet elucidated. In the present study, we determined the expression of major SR Ca²⁺ handling proteins in atria of human AF patients and in human and in a mouse model of heart failure (HF). We found that the expression of SR Ca²⁺ uptake and Ca²⁺ release channel proteins are significantly decreased in atria but not in the ventricles of pressure-overload induced HF in mice. In human AF and HF, the expression of SLN protein was significantly decreased; whereas the expressions of other major SR Ca²⁺ handling proteins were not altered. Further, we found that the SR Ca²⁺ uptake was significantly increased in human AF. The selective downregulation of SLN and enhanced SR Ca²⁺ uptake in human AF suggest that SLN downregulation could play an important role in abnormal intracellular Ca²⁺ cycling in atrial pathology.