Background: VM-1500 is the pro-drug of the active compound VM-1500A, a potent, highly selective NNRTI. Its antiviral profile is superior to that of efavirenz and other currently marketed NNRTIs. The PK profile suggests once daily dosing. Together with minimal side effects, VM-1500 may be a good NNRTI to be started in HIV treatment. Methodology: A randomized, placebo-controlled, multiple dose, double-blind study for 7 days in patients with HIV infection who are antiretroviral therapynaive with HIV-1 RNA > 5,000 copies/ml and CD4 > 250 cells/mm3. Eight patients were randomized to VM-1500 (20 mg) or placebo (7:1). After positive DSMB review the dose was escalated from 20 mg to 40 mg. A second cohort of 8 patients was randomized to VM-1500 (40 mg) or placebo (7:1). Results: Seven patients who received 20 mg of VM-1500 for 7 days the average HIV-1 RNA decreased from 82,944 copies/ml to 2,133 copies/ml while one patient who received placebo, HIV-1 RNA was 303,000 copies/ml at day 1 and 248,000 copies/ml at days 8. The average CD4 increased from 551 cells/mm3 to 592 cells/mm3 in VM-1500 group and the CD4 of one patient in placebo arm was 492 cells/mm3 at day 1 and 517 cells/mm3 at day 8. For the second cohort with VM-1500 40 mg, 7 patients who received 40 mg of VM-1500 for 7 days the average HIV-1 RNA decreased from 93,671 copies/ ml to 1,316 copies/ml while one patient who received placebo, HIV-1 RNA was 126,000 copies/ml at day 1 and 116,206 copies/ml at days 8. The average CD4 increased from 471 cells/mm3 to 525 cells/mm3 in VM-1500 group and the CD4 of one patient in placebo arm was 424 cells/mm3 at day 1 and 388 cells/mm3 at day 8. For the side effects, 3 patients in the first cohort (20mg) had mild dry mouth and polyuria, 1 patient had mild headache. However, patients in the second cohort (40mg) had no side effects for the whole seven days of VM-1500 treatment. Conclusions: VM-1500 showed excellent activity with a 1.8 log reduction in HIV-1 RNA after 7 days of treatment with only minimal side effects. VM-1500 is a good once daily candidate NNRTI to treat HIV-infected patients.