This paper presents a novel bio-inspired adaptive control technique that has been designed to maintain the performance of an aircraft under upset conditions. The proposed control approach is inspired by biological principles that govern the humoral response of the immune system of living organisms and is intended to reduce pilot effort while maintaining adequate aircraft operation outside bounds of nominal design. The immunity-based control parameters are optimized offline for multiple sets of failures using a genetic algorithm approach. The performance of the immunity-based augmentation is compared with a neural network (NN)-based augmentation. Different piloted tests were performed on a six degrees-of-freedom (6DOF) motion-based simulator for different types of maneuvers under several flight conditions. The results show that the artificial immune system (AIS) proposed scheme improves the aircraft handling qualities by reducing the tracking errors (TEs) and improving the pilot response required to maintain control of the aircraft under upset conditions.