The objective of this work is to compare anaerobic digestion of the organic fraction of municipal solid waste (OFMSW) and sanitary landfilling for combined heat and power (CHP) production, using biogas. The comparison aims to select the most appropriate method using economic, environmental, technological and legal criteria. In the first scenario considered, the total amount of 50,000 Mg/y (SI unit Mg = metric ton = tonne) commingled MSW is disposed of in a sanitary landfill. In the second scenario, 40% of OFMSW from 50,000 Mg/y of commingled MSW is source-separated and subject to dry, thermophilic, anaerobic digestion. The remainder MSW and the digestate are disposed of in a sanitary landfill. A sensitivity analysis for 100,000 and 200,000 Mg MSW/y was also conducted. For both methods, the appropriate CHP engines were selected, the amounts of produced biogas, energy, GHGs, NOx to the atmosphere, leachate production and the total capital and operation costs were calculated. Regression equations for total cost, net present value and gate fee were developed and used for economic assessment. Based on energy, environmental and legal criteria, CHP production from anaerobic digestion is favored, compared to sanitary landfilling. Based on economic criteria, anaerobic digestion is selected for MSW productions exceeding 210,000 Mg/y and 150,000 Mg/y, for the cases the investment is implemented with own funds or draws 55% from public funds, respectively. For smaller MSW productions, sanitary landfilling is favored, respectively. Although the results are based on Greek economic conditions, the comparison methodology can be applied to other countries.