Protein-protein interactions often involve secondary structural elements, such as helices. Protein-protein interactions within the Bcl-2 family are mediated by the helical BH3 domain of proapoptotic family members, such as Bad, Bak, Bax, or Bid. Here, we report that two 5-residue fragments located at the N- and C-termini of the 16-residue BH3 domain of Bad, respectively, serve as affinity-enhancing motifs (AEMs) for the BH3 domain. When added to the BH3 domain derived from other proapoptotic proteins such as Bak, Bax, or Bid, these AEMs significantly increased the Bcl-2-binding affinity of these BH3 peptides by promoting the helical structure. This finding may point to a new strategy for studying and mimicking helical peptide-protein interactions involved in apoptosis.