The class A adenosine A(1) receptor (A(1)R) is a G-protein-coupled receptor that preferentially couples to inhibitory G(i/o) heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 angstrom structure of the human A(1)R in complex with adenosine and heterotrimeric G(i2) protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A(1)R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A(1)R primarily via amino acids in the C terminus of the G alpha(i) alpha 5-helix, concomitant with a 10.5 angstrom outward movement of the A(1)R transmembrane domain 6. Comparison with the agonist-bound beta(2) adrenergic receptor G(s)-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A(1)R structure provides molecular insights into receptor and G-protein selectivity.