AbstractThe best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K⁺ current (I_K1) and Na⁺/K⁺ pump (I_NaK) densities (I_K1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF^–1; I_NaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF^–1; sustained vs. un‐sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher I_K1 (median density 0.12 ± 0.02 S mF^–1) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L‐type Ca²⁺ current, I_CaL, density 0.08 ± 0.03 S mF^–1). This atrial refractoriness, modulated by I_CaL and fast Na⁺ current (I_Na), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median I_CaL density 0.13 ± 0.05 S mF^–1). For short refractoriness, atria with high I_Na (median density 8.92 ± 2.59 S mF^–1) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low I_Na (median density 5.33 ± 1.41 S mF^–1). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. imageKey points Atrial fibrillation (AF) maintenance is facilitated by small L‐type Ca²⁺ current (I_CaL) and large inward rectifier K⁺ current (I_K1) and Na⁺/K⁺ pump. In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher I_K1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low I_CaL) Vernakalant is effective in atria presenting long refractoriness (high I_CaL). For short refractoriness, atria with fast Na⁺ current (I_Na) up‐regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low I_Na. The inward currents (I_CaL and I_Na) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.