The paper concerns with the global well-posedness issue of the 2D incompressible inhomogeneous Navier-Stokes (INS) equations with fractional dissipation and rough density. We first establish the L q t (L p )-maximal regularity estimate for the generalized Stokes system with fractional dissipation, and then we employ it to obtain the global existence of solution for the 2D fractional INS equations with large velocity field, provided that the L 2 ∩ L ∞ -norm of density minus constant 1 is small enough. Moreover, by additionally assuming that the density minus 1 is sufficiently small in the norm of some multiplier spaces, we prove the uniqueness of the constructed solution by using the Lagrangian coordinates approach. We also consider the density patch problem for the 2D fractional INS equations, and show the global persistence of C 1,γregularity of the density patch boundary when the piecewise jump of density is small enough.2010 Mathematics Subject Classification. Primary 35Q30, 76D05, 35B40. Key words and phrases. fractional inhomogeneous Navier-Stokes equations; maximal regularity; Lagrangian coordinates method; density patch. however, the system (1.2) has additional uniform bounded quantity, that is, the vorticity ω = curl u is uniformly bounded, which makes the L 2 -energy supercritical α < 1 case be globally well-posed.