Introduction: A controlled-release hydrocodone/acetaminophen (HC/APAP CR) tablet (15/500 mg) was developed for patient convenience. This study evaluated the pharmacokinetics of HC/APAP CR tablets in healthy subjects. Materials and Methods: This IRB-approved, two-part, single- and multiple-dose(s), fasting and non-fasting, open-label, randomized crossover study was conducted in 44 healthy adults. In Cohort 1, 24 subjects were randomized to receive a single-dose of 1, 2 and 3 HC/APAP CR tablets and 3 doses of HC/APAP reference (10/325 mg) every 4-hours under fasting conditions. In Cohort 2, 20 subjects were randomly assigned to 2 HC/APAP CR tablets administered every 12-hours and 1 HC/APAP reference tablet administered every 4 hours for 3 days. Washout intervals of at least 5 days separated the doses of each period. Results: Following a single-dose of 1, 2 and 3 HC/APAP CR tablet(s), the mean maximum plasma concentration (C_max) ranged from 13.3 to 36.8 ng/mL for HC and 2.01 to 6.68 μg/mL for APAP; the area under the plasma concentration-time curve (AUC_ω) ranged from 232 to 658 ng*h/mL for HC and 21.9 to 63.7 μg*h/mL for APAP. Systemic exposures (C_max and AUC_ω) of HC and APAP increased proportionally with increasing doses. The mean time to reach C_max (T_max) was 6.0-6.7 hours for HC and 1.1-1.3 hours for APAP. Following twice-daily dosing of 2 HC/APAP CR tablets for 3 days, steady state for HC/APAP concentrations was attained by 24 hours. The mean C_max on Day 3 was 37.0 ng/mL for HC and 4.96 μg/mL for APAP. The adverse event profile was consistent with that expected of opioid-naive subjects receiving opioid-combination therapy. Conclusions: Systemic exposures of HC and APAP demonstrated a dose-proportional increase from 1 to 3 tablets. Steady-state concentrations were reached by 24 hours with minimal accumulation following twice-daily administration. The pharmacokinetics of HC/APAP CR tablets support a twice-daily dosage regimen.