Rhodesain is the main cysteine protease ofTrypanosoma brucei rhodesiense, the parasite causing the acute lethal form of Human African Trypanosomiasis. Starting from the dipeptide nitrileCD24, the further introduction of a fluorine atom in themetaposition of the phenyl ring spanning in the P3 site and the switch of the P2 leucine with a phenylalanine led toCD34, a synthetic inhibitor that shows a nanomolar binding affinity towards rhodesain (Ki= 27 nM) and an improved target selectivity with respect to the parent dipeptide nitrileCD24. In the present work, following the Chou and Talalay method, we carried out a combination study ofCD34with curcumin, a nutraceutical obtained fromCurcuma longa L.Starting from an affected fraction (fa) of rhodesain inhibition of 0.5 (i.e., the IC50), we observed an initial moderate synergistic action, which became a synergism for favalues ranging from 0.6 to 0.7 (i.e., 60–70% inhibition of the trypanosomal protease). Interestingly, at 80–90% inhibition of rhodesain proteolytic activity, we observed a strong synergism, resulting in 100% enzyme inhibition. Overall, in addition to the improved target selectivity ofCD34with respect toCD24, the combination ofCD34+ curcumin resulted in an increased synergistic action with respect toCD24+ curcumin, thus suggesting that it is desirable to useCD34and curcumin in combination.