Nitric oxide (NO) synthesized by macrophages is cidal to Leishmania. Since NO diffuses into tissues, we reasoned that NO-generating creams applied topically to lesions might be an effective and inexpensive treatment for cutaneous leishmaniasis (CL). NO was generated non-enzymatically by the acidification of nitrite (KNO 2 ) by ascorbic acid (ASC) or salicylic acid (SAL). Experiments in vitro showed that the combinations of KNO 2 and SAL, ASC, or KC1 all killed promastigotes and amastigotes of L. major in a dose- and time-dependent manner, but were toxic to macrophages at higher concentrations. Experiments in vivo showed modest efficacy of the combinations applied topically to L. major CL lesions of BALB/c mice. Forty patients with parasitologically proven L. tropica CL from Aleppo, Syria, were treated for 4 weeks with KNO 2 in aqueous cream combined with KC1, ASC, or SAL. Only 11 (28%) of 40 patients showed improvement and only 5 (12%) of 40 were cured at 2 months. Further development of NO-generating creams is warranted.