The coordination features of the two dipyridine-containing polyamine macrocycles 2,5,8,11,14-pentaaza-(2,2′)[1,15]-bipyridylophane (L1) and 4,4′-(2,5,8,11,14-pentaaza-(2,2′)-bipyridylophane) (L2) toward Cu(II) and Ni(II) have been studied by means of potentiometric and spectrophotometric UV-vis titrations in aqueous solutions. While in L1 all the nitrogen donor atoms are convergent inside the macrocyclic cavity, in L2 the heteroaromatic nitrogen atoms are located outside. Ligands L1 and L2 form stable mono- and dinuclear complexes with Cu(II). In the case of Ni(II) coordination, only L1 gives dinuclear complexes, while L2 can form only mononuclear species. In the Cu(II) or Ni(II) complexes with L1 the metal(s) are lodged inside the macrocyclic cavity, coordinated to the heteroaromatic nitrogens. As shown by the crystal structure of the [CuL1]2+ and [NiL1]2+ cations, at least one of the two benzylic nitrogens is not coordinated and facile protonation of the complex takes place at neutral or slightly acidic pH values. The particular molecular architecture of L2, which displays two well-separated binding moieties, strongly affects its coordination behavior. In the mononuclear [CuL2]2+ complex, the metal is encapsulated inside the cavity, not coordinated by the dipyridine unit. Protonation of the complex, however, occurs on the aliphatic polyamine chain and gives rise to translocation of the metal outside the cavity, bound to the heteroaromatic nitrogens. In the [NiL2]2+ complex the metal is coordinated by the dipyridine nitrogens, outside the macrocyclic cavity. Thermodynamic and/or kinetic considerations may explain the different behavior with respect to the corresponding Cu(II) complex.