The essay is focused on the idea that the content considered to be intrinsic to the principle of presumption of guilt is the product of specific ideological choices, ranging between a higher sensitivity to social defence and individual guarantees. This is confirmed by the historical social debate in Italy, by the classical school up to the Republican Constitution, by the ideas of the positivist school and those of the technical-juridical school. Then the work opens to a comparative perspective, by analyzing certain aspects of the presumption of guilt in some European state systems, both from a constitutional point of view and from the point of view of the disciplines specifically pertaining to the different juridical cultures; they leave us doubts about the legitimacy of normative and interpretation models, which seem to consider some elements of the cases in point as being implicit in the tangible fact or to be assessed by presumptions, with a possible inversion of the burden of proof. After an excursus about the homogeneizing role of the presumption of guilt within a supranational perspective, the research focuses on the case law of the European Court of Human Rights and of the European Court of Justice, highlighting some of its ambiguities and contradictions as regards the admission of “reasonable” waivers of the presumption of guilt as rule of evidence. The same critical observations are made as regards the proposal of EU directive about the consolidation of the idea of the presumption of guilt, which, instead, paradoxically seems to weaken its content of defence of civil rights. The research deals with some hypotheses undermining the principle by the help of the substantive penal law, such as the ideas of presumed danger or intention and guilt, underlining, on the contrary, the necessity of an integrated vision of the penal system, imposing a model of trial being consistent with that of the substantive law defending civil rights. Conclusions are devoted to the risk, due to misunderstood punishment efficiency, of a substantially new interpretation, from a probative point of view, of substantive penal guarantees showing how the case law and European norms in course of development can influence this. Finally they also deal with the critical points and ambiguities in the evaluation of the reasonableness of waivers of the principle and in the balance between social defence and individual guarantees made according to equivocal and incontrollable parametres leaving space to illegitimate solutions.