Based on the analytical method, the failure function is obtained for reinforced concrete (RC) frame columns with large eccentric compression under vertical and horizontal loads together. A special characteristic is found that the whole correlative curve of vertical and horizontal loads may contain some rising parts under limit state, and the corresponding determinant condition is also proposed. With the approximate linearization of rising parts, the practical limit state function is also obtained. Then, the seismic reliability is calculated for RC frame columns with large eccentric compression under different combined ratios of gravity and horizontal earthquake loads according to the current Chinese design code. The results indicate that its reliability is lower than the reliability of RC frame beam when the strong column coefficient adopts low values. This provides some useful references for engineers to design RC columns with large eccentric compression reasonably.