Natriuretic peptides (NPs) may regulate adipocyte metabolism including adiponectin. Infusion of atrial natriuretic peptide (ANP) increases plasma adiponectin in patients with heart failure. However, this relation has not been examined in a clinical setting or in myocardial infarction (MI). Accordingly, we investigated the interplay between proANP and adiponectin and the prognostic implications in patients with MI. We prospectively included 680 patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention from September 2006 to December 2008. Blood samples were drawn immediately before percutaneous coronary intervention. Additionally, we included 40 patients with 4 obtained blood samples during STEMI. Adiponectin and proANP were measured in all plasma samples. All patients were followed for 5 years. End points were all-cause mortality (n = 137) and the combined end point (n = 170) of major adverse cardiovascular events (MACEs). Plasma adiponectin and proANP were strongly associated at admission (r = 0.34, p <0.001). In patients with increasing proANP during STEMI, adiponectin also increased (0.5 ± 0.3 vs −0.1 ± 0.1 mg/L, p = 0.026). During follow-up, patients with higher adiponectin at admission had increased risk of all-cause mortality and MACE (both, p <0.001). After adjustment for confounding risk factors by Cox regression analysis, adiponectin remained an independent predictor of all-cause mortality and MACE: hazard ratio 1.31 (95% confidence interval 1.07 to 1.60; p = 0.009) and 1.31 (95% confidence interval 1.09 to 1.57; p = 0.004), respectively, for each SD increase. However, the association vanished when proANP was included in the analysis. In conclusion, adiponectin is associated with an increased risk of all-cause mortality and MACE. However, concomitantly elevated proANP levels appear to confound the association between adiponectin and worsened outcome.