Cyclam macrocycles tetrasubstituted with amino-, thiourea-, and sugar-terminated side chains are ionized by electrospray ionization mass spectrometry (ESI-MS) as singly or doubly protonated species or as transition-metal complexes. Their fragmentation behavior is examined in a Fourier-transform ion-cyclotron-resonance (FT-ICR) mass spectrometer by collision-induced dissociation (CID) experiments. Typically, fragmentation occurs within the side chains through a number of different 1,2-elimination reactions irrespective of the absence or presence of a transition metal ion such as Co2+, Ni2+, or Zn2+. A remarkable exception is Cu2+, which induces ring cleavage reactions. This is traced back to an electron transfer from the cyclam nitrogen atoms to the Cu2+ ion. The electron transfer creates a cation-radical within the macrocycle, which induces typical fragmentation reactions such as α-cleavages that lead to fragmentation within the macrocycle. This interpretation is in line with fragmentation experiments on unsubstituted cyclam and its complexes.