Inward rectifier potassium currents I_K1 and acetylcholine activated I_K,ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I_K,ACh develops a receptor-independent, constitutively active component that together with increased I_K1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I_K1 and I _K,ACh in patients with and without cAF. I_K1 and I _K,ACh were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2∈μM) was employed to activate I_K,ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on I_K1. In contrast, all tested drugs inhibited CCh-activated I _K,ACh in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at -80 mV, -15.2∈±∈1.2 pA/pF, n∈=∈88/35 vs. -6.5∈±∈0.4 pA/pF, n∈=∈194/58 [myocytes/patients]; P∈<∈0.05), whereas CCh-activated I_K,ACh was smaller (-4.1∈±∈0.5 pA/pF vs. -9.5∈±∈0.6 pA/pF; P∈<∈0.05). In cAF, receptor-independent constitutive I_K,ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I_K,ACh channels. In cAF, all tested drugs reduced CCh-activated I_K,ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I _K,ACh, suggesting that they may block I_K,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I _K,ACh.