Objectives Although trends in opioid-related death rates in the United States have been described, the association between state-level opioid overdose death rates in early waves and substance-related overdose death rates in later waves has not been characterized. We examined the relationship between state-level opioid overdose death rates at the beginning of the crisis (1999-2004) and overdose death rates for opioids and other substances in later years. Methods Using 1999-2018 multiple cause of death data from the Centers for Disease Control and Prevention, we first categorized each state by quartile of baseline (1999-2004) opioid overdose death rates. By baseline opioid overdose death rates, we then compared states’ annual overdose death rates from any opioid, heroin, synthetic opioids, sedatives, stimulants/methamphetamine, and cocaine from 2005 through 2018. To test the association between baseline opioid overdose death rates and subsequent substance-related overdose death rates for all 6 substances, we estimated unadjusted and adjusted linear models controlling for annual state-level unemployment, median household income, age, sex, and race/ethnicity. Results Our results suggest 2 characteristics of the opioid crisis: persistence and pervasiveness. In adjusted analyses, we found that for each additional opioid overdose death per 100 000 population at baseline, states had 23.5 more opioid deaths, 4.4 more heroin deaths, 8.0 more synthetic opioid deaths, 9.2 more sedative deaths, 3.3 more stimulant deaths, and 4.6 more cocaine deaths per 100 000 population from 2005 to 2018. Conclusion These findings have important implications for continued surveillance to assist policy makers in deciding how to deploy resources to combat not just opioid use disorder but also polysubstance use disorder and broader problems of substance use disorder.