Nationally representative rates of incident prescription opioid use in the United States adult population and selected subpopulations are unknown. Using the National Health Interview Survey (2019–2020) longitudinal cohort, a cohort with 1-year follow-up created using random cluster probability sampling of noninstitutionalized civilian U.S. adults, we estimated rates and predictors of incident opioid use. Of 21,161 baseline (2019) participants randomly chosen for follow-up, the final analytic sample included 10,415 who also participated in 2020. Exposure variables were selected per the socio-behavioral model of health care utilization: predisposing characteristics (sex, age, race, etc), enabling characteristics (socioeconomic status, insurance status), health status (pain, disability, comorbidities, etc), and health care use (office visits, emergency room visits, and hospitalizations). Among adults who did not use prescription opioids in 2019, a 1-year cumulative incidence of 4.1% (95% confidence interval [CI]: 3.5–4.6) was seen in 2020, with an incidence rate (IR) of 32.6 cases of new prescription opioid use per 1,000 person-years (PYs). Cumulative incidence, IR, and adjusted relative risk (RR) varied by participant characteristics. We observed the highest IR in those with ineffective pain treatment (81.6 cases per 1,000 PY) and those who visited the emergency room ≥3 times (93.8 cases per 1,000 PY). Participants reporting ≥4 painful conditions had an adjusted RR of 2.9 (95% CI: 2.0–4.1), while the RR for those with sleep problems was 2.3 (95% CI: 1.7–3.1). Overall, this study presents nationally representative rates of incident prescription opioid use and suggests that some participants are using prescription opioids as an early-resort analgesic contrary to best-practice guidelines. PerspectiveThis longitudinal cohort study presents nationally representative rates of incident prescription opioid use in U.S. adults and selected subpopulations. Our data suggest that some participants are using prescription opioids as a first-line or early-resort analgesic, contrary to best-practice guidelines.