In the USA, homicide is a leading cause of death for young males and a major cause of racial disparities in life expectancy for men. There are intense debate and little rigorous research on the effects of firearm sales regulation on homicides. This study estimates the impact of Missouri’s 2007 repeal of its permit-to-purchase (PTP) handgun law on states’ homicide rates and controls for changes in poverty, unemployment, crime, incarceration, policing levels, and other policies that could potentially affect homicides. Using death certificate data available through 2010, the repeal of Missouri’s PTP law was associated with an increase in annual firearm homicides rates of 1.09 per 100,000 (+23%) but was unrelated to changes in non-firearm homicide rates. Using Uniform Crime Reporting data from police through 2012, the law’s repeal was associated with increased annual murders rates of 0.93 per 100,000 (+16%). These estimated effects translate to increases of between 55 and 63 homicides per year in Missouri.