Adsorption of H2S on the Ni2(dhtp)(H2O)2·8H2O metal−organic framework (known as CPO-27-Ni or MOF-74-Ni) is characterized by in situ powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR), Raman, and UV−visible spectroscopy) and by first-principles periodic boundary conditions calculations. PXRD results show very high stability of CPO-27-Ni framework in the presence of H2S. Nevertheless, as evidenced by change in color of the sample from pale yellow to dark green, the adsorption of H2S strongly affects the coordination of Ni sites. FTIR results show the reversible molecular adsorption of H2S. Experimental and computed energies of interaction reveal good agreement. Quantitative data considering energetic aspects (calorimetric measurements) are also included. This work highlights the fundamentals of H2S adsorption onto the CPO-27-Ni framework.