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In this paper, we focus on the existence of positive solutions for a singular tempered sub-diffusion fractional model involving a quasi-homogeneous nonlinear operator. By using the spectrum theory and computing the fixed point index, some new sufficient conditions for the existence of positive solutions are derived. It is worth pointing out that the nonlinearity of the equation contains a tempered fractional sub-diffusion term, and is allowed to possess strong singularities in time and space variables. In particular, the quasi-homogeneous operator is a nonlinear and non-symmetrical operator.