Deep low-permeability clay layers are considered as safe environments for disposal of high-level radioactive waste. In Belgium, the Boom Clay is a candidate host rock for deep geological disposal. In this study, we analyze the effects of fractures and spatially variable hydraulic conductivity on radionuclide migration through the clay. Fracture geometry and properties are simulated with Monte Carlo simulation. The heterogeneity of hydraulic conductivity is simulated by direct sequential co-simulation using measurements of hydraulic conductivity and four types of secondary variables. The hydraulic conductivity and fracture simulations are used as input for a transport model. Radionuclide fluxes computed with this heterogeneous model are compared with fluxes obtained with a homogeneous model. The output fluxes of the heterogeneous model differ at most 8% from the homogeneous model. The main safety function of the Boom Clay is thus not affected by the fractures and the spatial variability of hydraulic conductivity.