The entropy generation based on the second law of thermodynamics is investigated for turbulent forced convection flow of ZrO2-water nanofluid through a square pipe with constant wall heat flux. Effects of different particle concentrations, inlet conditions and particle sizes on entropy generation of ZrO2-water nanofluid are studied. Contributions from frictional and thermal entropy generations are investigated, and the optimal working condition is analyzed. The results show that the optimal volume concentration of nanoparticles to minimize the entropy generation increases when the Reynolds number decreases. It was also found that the thermal entropy generation increases with the increase of nanoparticle OPEN ACCESS Entropy 2014, 16 6117 size whereas the frictional entropy generation decreases. Finally, the entropy generation of ZrO2-water was compared with that from other nanofluids (including Al2O3, SiO2 and CuO nanoparticles in water). The results showed that the SiO2 provided the highest entropy generation.