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• A method of regional non-stationary flood frequency analysis is proposed. • The index incorporates climatic and reservoir factors as covariates. • MRI is more suitable for non-stationary flood frequency analysis. • The prediction period of flood frequency analysis is extended. Global climate change and reservoir regulations can alter the natural flow of rivers. Influenced by these two drivers, flood sequences may no longer satisfy the assumption of stationary, thereby making it difficult to accurately analysis flood frequency and to design water conservancy projects. Therefore, it is of great significance to analyse the non-stationary frequency of flood sequences in a changing environment. In this study, we proposed a method for conducting nonstationary flood frequency analysis caused by cascade reservoirs as well as the low-frequency climate indices. The proposed non-stationary model 2, with the explanatory variables of climate indices and modified reservoir index (MRI), was compared with the traditional stationary model and the widely used non-stationary model 1 with time as the explanatory variable. The study was conducted at six hydrological stations in the main stream and tributaries of the upper reaches of the Yangtze River in China (considered as the Three Gorges Reservoir Area). The results of the generalized additive model for location, scale and shape (GAMLSS) showed that the Akaike information criterion and Bayesian information criterion values of the proposed non-stationary model method 2 are smaller than those of the two comparison models. When the low-frequency South Oscillation Index is high or the Arctic Oscillation and North Pacific Oscillation are low, the stationary model underestimates the design value of flood quantiles compared with the non-stationary model 2. Compared with the non-stationary model 1, the MRI and low-frequency climate indices as the explanatory variables in model 2 can better describe the non-stationary characteristics of flood frequency and amplitude. In addition, the non-stationary model considering external physical factors can provide better prediction of future design flood compared with two traditional models. [ABSTRACT FROM AUTHOR]