Microreactor technology, an important method of process intensification, offers numerous potential benefits for the process industries. Fluid–fluid reactions with mass transfer limitations have already been advantageously carried out in small-scale geometries. In liquid–liquid microstructured reactors (MSR), alternating uniform slugs of the twophase reaction mixture exhibit well-defined interfacial mass transfer areas and flow patterns. The improved control of highly exothermic and hazardous reactions is also of technical relevance for large-scale production reactors. Two basic mass transfer mechanisms arise: convection within the individual liquid slugs and diffusion between adjacent slugs. The slug size in liquid–liquid MSR defines the interfacial area available for mass transfer and thus the performance of the reactor. There are two possibilities in a slug flow MSR depending on the interaction of the liquids with the solid wall material: a dispersed phase flow in the form of an enclosed slug in the continuous phase (with film—complete wetting of the continuous phase) and an alternate flow of two liquids (without film—partial wetting of the continuous phase). In the present work, a computational fluid dynamics (CFD) methodology is developed to simulate the slug flow in the MSR for both types of flow systems. The results were validated with the experimental results of Tice et al. (J.D. Tice, A.D. Lyon and R.F. Ismagilov, Effects of viscosity on droplet formation and mixing in microfluidic channels, Analytica Chimica Acta 507 (1) (2004), pp. 73–77.).