Microstructure instabilities of the fully lamellar Ti-45Al-8.5Nb-(W,B,Y) alloy were investigated by SEM and TEM after long-term thermal cycling(500 and 1000 thermal cycles) at 900 °C. Two major categories of microstructure instability were produced in the alloy after the thermal cycling: 1) The discontinuous coarsening implies that grain boundary migrations are inclined to occur in the Al-segregation region after the long-term thermal cycling, especially after 1000 thermal cycles. Al-segregation can be reduced during the process of long-term thermal cycling as a result of element diffusion; 2) The α2 lamellae become thinner and are broken after 1000 thermal cycles caused by the dissolution of α2 lamellae through phase transformation of α2→γ. The γ grains nucleate within the α2 lamellae or(α2+γ) lamellae in a random direction.