The effect of structural imperfections as well as oxygen impurities on the quantum conductance of poly(3-hexylthiophene) is calculated from first-principles by solving the scattering problem for molecular structures obtained within density functional theory. It is shown that the conductivity of molecular crystals perpendicular to the polymer chains depends strongly on the stacking geometry and is roughly described within the Wentzel-Kramers-Brillouin approximation. Furthermore, it is found that local relaxation for twisted or bent polymer chains efficiently restores the conductance that drops substantially for sharp kinks with curvature radii smaller than 17 Å and rotations in excess of ∼60°. In contrast, isomer defects in the coupling along the chain direction are of minor importance for the intrachain transmission. Also, oxidation of the side chains as well as molecular sulfur barely changes the coherent transport properties, whereas oxidation of thiophene group carbon atoms drastically reduces the conductance.