In this paper, we interpret the 750 GeV diphoton excess in the Zee-Babu extension of the two-Higgs-doublet model by introducing a top partner ($T$)/bottom partner ($B$). In the alignment limit, the 750 GeV resonance is identified as the heavy CP-even Higgs boson ($H$), which can be sizably produced via the QCD process $pp to Tbar{T}$ or $pp to Bbar{B}$ followed by the decay $Tto Ht$ or $B to Hb$. The diphoton decay rate of $H$ is greatly enhanced by the charged singlet scalars predicted in the Zee-Babu extension and the total width of $H$ can be as large as 7 GeV. Under the current LHC constraints, we scan the parameter space and find that such an extension can account for the observed diphoton excess.
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