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Background: KP-1461 is a prodrug to KP-1212. KP-1212 is a viral mutagen designed to increase viral error rate. Methods: We describe 2 phase I studies: KP1461-101 (double-blind, placebo-controlled, single, escalating doses, 100 to 1600 mg study in 42 non-HIV-infected participants) and KP-1461-102 (double-blind placebo-controlled dose escalation 14-day study in HIV-infected participants, 400-3200 mg). Primary objectives were safety/tolerability. Secondary objectives included pharmacokinetic analysis with exploratory objective to characterize KP-1212 effects on viral load. Results: KP-1461 was well tolerated. Majority of adverse events were grade 1 (neurological, gastrointestinal, cardiovascular). Four participants experienced grade 3 and 1 experienced a grade 4 event. Analysis demonstrated no difference in pharmacokinetic parameters at day 1 or 14. Linear pharmacokinetics found in 1600 mg arm. Compared to placebo, only at the 3200 mg dose demonstrated a marginally statistically significant virologic response. Conclusions: These studies provide safety/tolerability information and suggest virologic efficacy. KP-1212, a first-in-class antiretroviral, demonstrates the ability to induce viral eradication in vitro . Viral reduction in vivo may foretell a paradigm shift in HIV pharmacotherapy.