The effect of slag composition on the cleanliness of Al-Ti deoxidized interstitial-free steel produced via basic oxygen furnace (BOF)-ladle furnace (LF)-Ruhrstahl-Heraeus (RH)-continuous casting (CC) process was investigated by the systematic samplings and analyses for four heats in a steel plant in China. Oxygen/nitrogen analyzer, automatic scanning electron microscope, field-emission scanning electron microscope, and energy spectroscopy analysis were used to analyze the variations of number, size, type, and morphology of inclusions in molten steel from RH to tundish, and X-ray fluorescence was used to analyze the slag composition. The relationship between slag composition and inclusion characteristics in molten steel was investigated. The effect of slag composition on the oxygen mass transfer from the slag–metal interface to liquid steel was also studied through a theoretical calculation. The results showed that the cleanliness of molten steel was greatly affected by the slag composition. The deterioration of steel cleanliness was mainly arisen from a serious reoxidation of molten steel by oxidizing components like (T.Fe + MnO) in top slag during RH refining process. A weak ability to absorb inclusions of top slag with high CaO/Al2O3 and CaO/SiO2 mass ratios was confirmed from the inclusions analyses. The size and number of Al2O3 inclusion clusters were larger, and Ti content in Al2O3-TiO x inclusions was higher from RH to tundish in the case of serious reoxidation. The reduction of FeO content and keeping the CaO/Al2O3 and CaO/SiO2 ratios at about 1.6 and 4–7, respectively, in top slag during RH refining process was beneficial to minimize the reoxidation of Al and Ti and increase the inclusion absorption ability of top slag.