Peptides characterized by single or multiple N-methylated, C(alpha)-trisubstituted (e.g., protein) amino acids are of great interest in medicinal chemistry. Several naturally occurring peptides, remarkably stable to enzymatic attacks, are based on N-methylated residues. The classical conditions (CH(3)I/Ag(2)O in DMF, 24 h, room temperature) for N-methylation of the peptide function are useful tools for distinguishing solvent exposed from intramolecularly H-bonded -CO-NH- groups in peptides. In this work we have extended this reaction to N(alpha)-acylated, linear peptides based exclusively on helicogenic C(alpha)-tetrasubstituted alpha-amino acids, e.g., Aib (alpha-aminoisobutyric acid) or (alphaMe)Nva (C(alpha)-methyl norvaline) residues. Under the experimental conditions used, only amide monomethylation (on the N-terminal, acylated, residue) takes place. Methylation of internal peptide groups linking two C(alpha)-tetrasubstituted residues was not observed. Our FT-IR absorption, NMR, and X-ray diffraction investigations support the view that the beta-turn and 3(10)-helical conformations preferred by the original peptides are not dramatically perturbed in the derivatives monomethylated at position 1. In particular, the tertiary amide bonds are trans. Conversely, the packing modes in the crystals are strongly influenced by the reduction of the number of H-bonding donors. The MeXxx-Xxx peptide bond is readily disrupted under mild acidic conditions.