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Heavy-metal-free silver based I-III-VI semiconductor nanocrystals (NCs), including ternary silver indium sulfide (AgInS2) and derivative quaternary silver indium zinc sulfide (i.e., AgInZn2S4) NCs, possess advantages of low toxicity, and size-tunable band gaps approaching near-infrared spectral range, which make them candidates for use in optoelectronic and biological devices. Herein, we report syntheses of AgInS2 based NCs starting from In2S3 template, which have been performed both in organic and aqueous phase through cation exchange. As a result, ternary silver indium sulfide and quaternary silver indium zinc sulfide NCs are obtained in both organic and aqueous media, and confirmed to be orthorhombic AgInS2 NCs and hexagonal AgInZn2S4 NCs, respectively. Furthermore, the aqueous AgInZn2S4 NCs with red emission and low cytotoxicity are explored for the cancer cell imaging.