Small-scale combined heat and power (CHP) plants present lower electric efficiency in comparison to large scale ones, and this is particularly true when biomass fuels are used. In most cases, the use of both heat and electricity to serve on-site energy demand is a key issue to achieve acceptable global energy efficiency and investment profitability. However, the heat demand follows a typical daily and seasonal pattern and is influenced by climatic conditions, in particular in the case of residential and tertiary end users. During low heat demand periods, a lot of heat produced by the CHP plant is discharged. In order to increase the electric conversion efficiency of small-scale micro-gas turbine for heat and power cogeneration, a bottoming organic Rankine cycle (ORC) system can be coupled to the cycle, however, this option reduces the temperature and the amount of cogenerated heat available to the thermal load. In this perspective, the paper presents the results of a thermo-economic analysis of small-scale CHP plants composed of a micro-gas turbine (MGT) and a bottoming ORC, serving a typical residential energy demand. For the topping cycle, three different configurations are examined: (1) a simple recuperative micro-gas turbine fueled by natural gas (NG); (2) a dual fuel externally fired gas turbine (EFGT) cycle, fueled by biomass and natural gas (50% share of energy input) (DF); and (3) an externally fired gas turbine (EFGT) with direct combustion of biomass (B). The bottoming ORC is a simple saturated cycle with regeneration and no superheating. The ORC cycle and the fluid selection are optimized on the basis of the available exhaust gas temperature at the turbine exit. The research assesses the influence of the thermal energy demand typology (residential demand with cold, mild, and hot climate conditions) and CHP plant operational strategies (baseload versus heat-driven versus electricity-driven operation mode) on the global energy efficiency and profitability of the following three configurations: (A) MGT with cogeneration; (B) MGT+ ORC without cogeneration; and (C) MGT+ORC with cogeneration. In all cases, a back-up boiler is assumed to match the heat demand of the load (fed by natural gas or biomass). The research explores the profitability of bottoming ORC in view of the following trade-offs: (i) lower energy conversion efficiency and higher investment cost of biomass input with respect to natural gas; (ii) higher efficiency but higher costs and reduced heat available for cogeneration with the bottoming ORC; and (iii) higher primary energy savings and revenues from feed-in tariff available for biomass electricity fed into the grid.