This work investigates the effect of Reynolds number, nanoparticle volume ratio, nanoparticle size and entrance temperature on the rate of entropy generation in Al2O3 /H2O nanofluid flowing through a pipe in the turbulent regime. The Reynolds average Navier-Stokes and energy equations were solved using the standard k-ε turbulent model and the central composite method was used for the design of experiment. Based on the number of variables and levels, the condition of 30 runs was defined and 30 simulations were run. The result of the regression model obtained showed that all the input variables and some interaction between the variables are statistically significant to the entropy production. Furthermore, the sensitivity analysis result shows that the Reynolds number, the nanoparticle volume ratio and the entrance temperature have negative sensitivity while the nanoparticle size has positive sensitivity.