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Drosotoxin is an engineered tetrodotoxin-resistant (TTX-R) sodium channel-specific blocker with a non-toxic structural core (Zhu et al. Biochem Pharmacol 2010; 80:1296–302). Here, we report the discovery and functional characterization of a carboxyl-terminally truncated analogue of drosotoxin (named DrTx(1–42)) which selectively inhibited dorsal root ganglion (DRG) neuron TTX-R sodium current (INa) with an IC50 value of 1.74 ± 0.07 μM. Consistent with this effect, DrTx(1–42) significantly attenuates inflammatory hyperalgesia of mice in a formalin-induced pain model with stronger potency than indomethacin, a nonsteroidal anti-inflammatory and analgesic drug. Our mutational experiments indicate that the N-turn insertion is an essential functional determinant for the emergence of neurotoxicity from a non-toxic antifungal scaffold.