jats:p Michel Serres’s philosophy of entropy takes what he famously calls the ‘Northwest Passage’ between the sciences and the humanities. By contextualizing his approach to entropy and affirming the role of a philosophy of difference, this paper explores Serres’s approach by means of ‘entropic differences’. It claims that entropy – or rather, entropies – provide Serres with a paradigmatic case for critical translations between different domains of knowledge. From his early Hermès series, through to The Birth of Physics and later writings on social and ethical themes, he keeps thermodynamical and informational – or ‘hard’ and ‘soft’ – understandings of entropy apart, while simultaneously exploring their relation. By focusing on the systematic significance of Serres’s ‘entropic difference’, this paper shows how it unfolds not necessarily as an ontological difference but as an operative function between the history and philosophy of science, epistemology, and a theory of negentropic (inter)subjectivity. </jats:p>