Abstract: Cetyl trimethyl ammonium chloride (CTAC) was used to modify montmorillonite (MMT) to prepare organic montmorillonite (CMMT). Then the complexes were used to absorb the 5-fluorouracil (5-FU) and coated with sodium alginate (SA). The performance of the release of the drug-loaded gels was measured, and the effects of pH and time on 5-FU release from the complexes were explored. Three models of in vitro drug release were used to simulate the release performance of 5-FU-loaded gels. The release mechanism of 5-FU from the gels and the feasibility of MMT as the sustained-release drug carrier were discussed. The results showed that CMMT/SA had the larger drug loading rate than MMT/SA, and the drug loading reached 0.6827 g/g. The release performance of 5-FU-loaded gels was mainly influenced by the pH value of media. The in vitro cumulative amount of 5-FU released from 5-FU/CMMT/SA at pH 7.4 reached 77.10%, and the lowest was at a pH value of 1.5. The first order kinetics model was better used to describe the variation of in vitro release rate of 5-FU with time at different pH values, compared to the Korsmeyer-Peppas and Higuchi models.