BACKGROUND The widely observed between-subject variability in cardiovascular responses to coffee may have a genetic basis. OBJECTIVE We evaluated acute blood pressure (BP) responses to caffeine and explored whether they are influenced by candidate gene variants affecting caffeine metabolism (for cytochrome P450 1A2), adenosine metabolism (for adenosine receptor and AMP deaminase), or catecholamine receptors. METHODS We recruited 110 healthy male habitual moderate coffee drinkers who refrained from drinking coffee on the day preceding the study. Each subject underwent ambulatory BP monitoring at 6-min intervals for 2 h. Each participant was administered, in a double-blind design, 40 mL of either a decaffeinated coffee preparation plus 3 mg caffeine/kg (caf) or the corresponding vehicle (decaf). The protocol was repeated 24 h later with the alternative preparation. Blood samples were collected for genetic and plasma caffeine and catecholamine evaluations. RESULTS Compared with decaf, caf was associated with a mean (± SD) significant increase in systolic BP of 4 ± 12 mm Hg and in diastolic BP of 3 ± 10 mm Hg (P < 0.001 for both). Plasma caffeine and adrenaline increased after caf, but not after decaf. Of 11 gene polymorphisms analyzed, a relation was observed between the ADORA2A TT variant and the change in SBP peak and between the ADRA2B I variant and the changes in both SBP mean and peak; mean peak change in SBP; these variants were associated with increased SBP responses to caf. CONCLUSIONS Variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α(2)-adrenergic receptors. This trial is registered at clinicaltrials.gov as NCT01330680.