This paper focuses on the seismic risk assessment of historic masonry towers according to the Italian "Guidelines for the Assessment and Mitigation of the Seismic Risk of the Cultural Heritage." The latter identifies a methodology of analysis based on three different levels of evaluation, according to increasing requirements on the structural knowledge: LV1 (analysis at territorial level), LV2 (local analysis), and LV3 (global analysis). Regardless of the methodology of analysis, the more advanced the achieved level of knowledge, the higher the reliability of these approaches becomes. In this field, a fundamental task is the estimation of the uncertain parameters (both material properties and boundary conditions) affecting the structural behavior. The effect of these uncertainties on the global structural response is herein approached through the discussion of an illustrative case study of some of the historic masonry towers in the city center of San Gimignano (Siena, Italy). The seismic risk of these towers was analyzed in the framework of Seismic Risk of Monumental Buildings (RiSEM is the Italian acronym), a research project granted by the Tuscany Regional Administration, and this paper summarizes the results obtained for two of the preceding three levels, which highlights a few issues concerning the seismic risk of historic masonry towers. Useful conclusions are drawn in order to quantify, when performing an LV3 approach through nonlinear models, the effects of the uncertainties on the seismic risk evaluation of such structural typology. The paper, in particular, confirms once more how strongly the effect of confinement reflected on tower seismic performances and stresses that specific attention should be paid to the definition of the effective portion of the structure to be considered as confined (with respect to adjacent buildings).