Glutaredoxins (Grxs), redox-active proteins with a typical -CPYC motif at their active sites, are involved in redox-regulatory processes and antioxidant defenses. The human malarial parasite Plasmodium falciparum possess a classical glutaredoxin (PfGrx) as well as a number of Grx-like proteins. In the present study, we investigated the unfolding energetics and conformational stability of PfGrx, using isothermal guanidine hydrochloride-induced and pH-dependent thermal denaturation. Reversible unfolding can be modeled using a two-state transition between the native and unfolded states. The structural topology of the protein was stable over a wide pH range from 3.0 to 11.0. Although the protein was thermally stable, it exhibited a small free energy of 1.56 kcal mol(-1) at 25 degrees C. The thermostability of PfGrx reached its maximum at pH 8.0, with a T(m) of 76.2 degrees C and a DeltaH(m) of 119 kcal mol(-1). To elucidate the factors underlying the thermostability, a protein stability curve was generated. Maximum stability occurred at around 47 degrees C, where the DeltaG_H2O(D) value was 4.30 kcal mol(-1). The high structural stability over a broad pH range, together with the capacity to endure very high temperatures, supports the notion that Grx can withstand a wide variety of conditions, allowing it to play a key role in cellular redox homeostasis. To the best of our knowledge, this work represents the first attempt to understand the energetic characteristics of a glutaredoxin in relation to accompanying structural changes.