We consider an effective field theory for a gauge singlet Dirac dark matter particle interacting with the standard model fields via effective operators suppressed by the scale Λ ≳ 1 TeV. We perform a systematic analysis of the leading loop contributions to spin-independent Dirac dark matter-nucleon scattering using renormalization group evolution between Λ and the low-energy scale probed by direct detection experiments. We find that electroweak interactions induce operator mixings such that operators that are naively velocity suppressed and spin dependent can actually contribute to spin-independent scattering. This allows us to put novel constraints on Wilson coefficients that were so far poorly bounded by direct detection. Constraints from current searches are already significantly stronger than LHC bounds, and will improve in the near future. Interestingly, the loop contribution we find is isospin violating even if the underlying theory is isospin conserving. DOI: 10.1103/PhysRevLett.112.191304 PACS numbers: 95.35.+d, 11.10.Gh, 11.10.Hi, 12.15.Lk Introduction.-A weakly interacting massive particle (WIMP) is an appealing dark matter (DM) candidate [1][2][3][4]. The lack of evidence for new physics at the Fermi scale motivates us to remain unbiased about the nature of DM and pursue model-independent approaches. Assuming that the DM is the only non-standard model (SM) particle experimentally accessible is not always justified at colliders [5][6][7], and simplified models have been recently proposed to overcome this limitation [8][9][10][11]. Nevertheless, besides very specific cases (e.g., inelastic DM [12]), it is an excellent approximation for direct searches given the small energy exchanged with the target nuclei. Within this approach, DM interactions with SM fields can be parameterized by higher dimensional operators suppressed by the cutoff scale Λ, with the main strength of providing model-independent relations among distinct null DM searches [13][14][15][16][17][18][19][20]. However, different search strategies probe different energy scales, and such a separation of scales may have striking consequences when a connection between different experiments or ultraviolet (UV) complete models with experiments is attempted. Indeed, in some cases loop corrections are known to dramatically alter direct detection (DD) rates [21][22][23][24][25][26][27][28][29].In this Letter we consider the case of a SM gauge singlet Dirac DM (χ), with m χ < Λ, and we calculate the complete set of one-loop effects induced by SM fields for operators up to dimension 6 that contribute to spin-independent (SI) DM-nucleon scattering. The separation between Λ and the DD scale is systematically taken into account via a proper renormalization group (RG) analysis. This procedure requires as a first step the computation of both electroweak (EW) and QCD running from the scale Λ to the EW symmetry breaking scale where threshold corrections are calculated and the heavy SM fields (Higgs boson, top quark, W and Z bosons) get integrated out, giv...