Background: Increasing accessibility of long-acting reversible contraceptive methods, like intrauterine devices (IUDs), is an important strategy to reduce the risk of unintended pregnancy. Unfortunately, concerns about pain with insertion is one of the major barriers to IUD use, especially among nulliparous women. To increase acceptance of this highly effective contraceptive, there is need to investigate novel, low cost, easily applied and accessible techniques to improve the insertion experience. Nitric oxide (NO) is a free radical molecule that mediates a wide range of physiologic processes, including cervical remodeling. Various NO donors administered vaginally and intracervically have been studied to provide cervical ripening for first trimester abortion and term labor induction with minimal side effects. Nitroprusside is the only NO donor that is readily available in the US in sterile form to be compounded into a sterile gel, stable at room temperature and inexpensive. We hypothesized that intracervical nitroprusside would remodel the cervix to allow clinically meaningful improvement in pain with IUD insertion with minimal side effects compared to placebo. Methods: We performed a randomized, double-blind, placebo controlled pilot study to evaluate the efficacy and tolerability of nitroprusside gel applied intracervically as an intervention to improve the IUD insertion experience for both patient and provider. A total of 24 nulliparous women were randomized to receive intracervical placebo or 10mg nitroprusside gel immediately prior to IUD placement. Subjects completed a series of 100mm visual analogue scales (VAS) at several time points. The primary outcome was subject-reported pain with IUD insertion. Secondary outcomes included provider-reported ease of insertion; subject-reported pain at other time points; adverse effects; and need for additional dilation. This pilot study had 82% power to detect a 30mm difference between groups with a one-sided alpha of 0.05. Results: Baseline characteristics were similar between randomization groups. The mean pain score with deployment of the IUD was 72.5 mm in the placebo group and 58.7 mm in the nitroprusside group (p=0.07, one-sided). A similar modest reduction in pain was seen with uterine sounding and passage of the IUD inserter through the cervix. All IUDs were successfully placed upon first attempt, with no difference in ease of insertion reported by providers. Two subjects required dilation, one in each group. There were two vasovagal reactions in the nitroprusside group, and none in the placebo group. Otherwise, there were no differences in blood pressure, pulse, or any side effects. Conclusions: Intracervical administration of 10mg nitroprusside gel immediately prior to IUD insertion appears to provide a modest reduction in pain with IUD insertion among nulliparous women. Further research is needed to clarify if the reduction in pain is significant enough to be able to recommend the routine use of this intervention.