The usefulness of targeted molecular dynamics (TMD) for the simulation of large conformational transitions is assessed in this work on the unfolding process of chymotrypsin inhibitor 2 (CI2). In TMD the force field is supplemented with a harmonic restraint which promotes either the increase of the conformational distance from the native state or the decrease of the distance from a target unfolded structure. As a basis of comparison, unfolding is also simulated by conventional, i.e., unrestrained, molecular dynamics at 375 and 475 K. In all simulations, an implicit approximation of solvation is used to adiabatically model the solvent response, which is appropriate for the nanosecond unfolding simulation method used here. In total, 44 TMD and 25 unrestrained high-temperature molecular dynamics simulations of CI2 unfolding were performed with an implicit solvation model that allowed more than 150 ns to be sampled. Qualitative agreement is found between the results of the TMD and unrestrained molecular dynamics at high temperature. The energies of the conformations sampled during TMD unfolding at 300 and 475 K are comparable to the ones obtained by conventional molecular dynamics at 375 and 475 K, respectively. The sequence of events, i.e., secondary and tertiary structure disruption, is similar in all unfolding simulations, despite the diversity of the pathways. Previous simulations of CI2 performed with different force fields and solvation models showed a similar sequence of events. This indicates that the TMD pathways are realistic even for very large conformational transitions such as protein unfolding.