With the increasing frequency of fire caused by construction materials, smoke toxicity evaluation plays a key role in related fields. Numerical simulation has become a popular method to predict the toxicity of smoke. A computational study of differential diffusion effects on smoke toxicity evaluation is proposed in this study. Further, an effective Lewis number model derived from the Reynolds-averaged form of the Navier-stokes (RANS) transport equations is proposed in turbulent flames. The accuracy of the study is illustrated for a polyurethane foam fire in a 1/5 scale vertical shaft. The temperature and the concentrations of smoke composition are mainly discussed. From the comparison of the calculations with the direct numerical simulations (DNS) data it is observed that the temperature and mass fractions of species agree well with the DNS data when differential diffusion effects are taken into account. On the other hand, these numerical results are overestimated if differential diffusion effects are neglected. The FED values indicate that differential diffusion has a strong influence on smoke toxicity evaluation when using N-Gas model.