Opioid misuse, abuse, and overdose are a rapidly growing public health epidemic. Medicaid Lock-In Programs (MLIPs) are designed to prevent overutilization of controlled substances by Medicaid patients. However, despite widespread use, there is little information on their effect. Using North Carolina (NC) Medicaid claims data from October 2008 through June 2013, we examined changes in Medicaid-reimbursed opioid prescriptions by patients enrolled in NC's MLIP. We used mixed effects models to examine the effect of MLIP enrollment on monthly opioid claims, number of pharmacies, total days' supply, total units (ie, pills), and total Medicaid payments for opioids. In our sample of 6,148 MLIP patients, the odds of having any opioid claim in a given month was 84% lower during MLIP enrollment relative to the period before enrollment (odds ratio = .16). MLIP enrollment also corresponded with a reduction in monthly number of opioid prescriptions by 1.13, monthly number of pharmacies by .61, and monthly Medicaid expenditures by $22.78. Although MLIPs may constitute a successful component of comprehensive efforts to reduce the potential overutilization of opioids, care should be taken to ensure that programs such as MLIPs do not constrain patients' legitimate needs for analgesic medications. PERSPECTIVE: Enrollment in NC's MLIP reduced the likelihood that patients would present a claim for an opioid prescription, and the number of opioid prescriptions patients secured each month. MLIPs may constitute a successful strategy for reducing the misuse, abuse, and diversion of prescription opioids. However, further research is needed to examine the program's potential unintended consequences.