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Due to the impact of both natural and human-induced changes, the hydrological regimes of many river deltas worldwide have been experienced either gradual or abrupt shifts. However, little work has explored the relative impacts of natural and human-induced changes on the natural balance of these delta systems. This study explores the overall influences of intensive human interventions (e.g., dam constructions, sand excavations, and land reclamations) on the relative mean sea level (RMSL) changes in the Pearl River Delta (PRD) in China. The analysis uses long-term measurements based on monthly averaged RMSL in 26 stations and reproduces the RMSL that would have occurred in the absence of large-scale human interventions by means of a simple bivariate linear regression model. Generally, we observe that the RMSL dynamics can be categorized into three distinct types, descending, ascending and fluctuant, according to the Mann-Kendall trend test. The analysis shows that the RMSL in the upper and central parts of the PRD displays a significant descending tendency owing to the deepening of the channels, which is primarily attributed to large-scale sand excavation. In contrast, for stations near the outlets, we observed an ascending tendency in RMSL that can be attributed to the combined effects of both the rise in global sea level and channel extension due to large-scale land reclamations. The regression model confirms that the human interventions have greater impacts in the upper and central parts of the PRD that feature river-dominated dynamics, compared with the lower parts of the PRD that are characterized by tide dominated dynamics. In addition, the simulated results display a marked seasonal alteration in the RMSL: the alteration induced by human interventions is apparently greater during the flood season than it is during the dry season. The proposed method used here to quantify the impacts of both natural and human-induced interventions on the RMSL is particularly useful for setting scientific guidelines for water managements (e.g., flood control and salt intrusion prevention) and regulation projects (e.g., dam constructions and land reclamation) in river deltas.