Aim: To examine associations of opioid use and pain interference with activities (PIA), healthcare resource utilization (HRU) and costs, and wage loss in noninstitutionalized adults with osteoarthritis in the United States (US).Methods: Adults with osteoarthritis identified from the Medical Expenditure Panel Survey for 2011/2013/2015 were stratified by no-opioid use with no/mild PIA, no-opioid use with moderate/severe PIA, opioid use with no/mild PIA, and opioid use with moderate/severe PIA. Outcomes included annualized total HRU, direct healthcare costs, and wage loss. Multivariable regression analyses were used for comparisons versus no-opioid use with no/mild PIA (referent). The counterfactual recycled prediction method estimated incremental costs. Results reflect weighted nationally representative data.Results: Of 4,921 participants (weighted n = 20,785,007), 46.5% had no-opioid use with no/mild PIA; 23.2% had no-opioid use with moderate/severe PIA; 9.6% had opioid use with no/mild PIA; and 20.7% had opioid use with moderate/severe PIA. Moderate/severe PIA and/or opioid use were associated with significantly higher HRU and associated costs, and wage loss. Relative to adults with no/mild PIA, opioid users with moderate/severe PIA were more likely to have hospitalizations, specialist visits, and emergency room visits (all p < .001). Relative to the referent, opioid use with no/mild PIA had higher per-patient incremental annual total healthcare costs ($11,672, 95% confidence interval [CI] = $11,435–$11,909) and wage loss ($1,395, 95% CI = $1,376–$1,414) as did opioid use with moderate/severe PIA ($13,595, 95% CI = $13,319–$13,871; and $2,331, 95% CI = $2,298–$2,363) (all p < .001). Compared with the referent, estimated excess national total healthcare costs/lost wages were $23.3 billion/$1.3 billion for opioid use with no/mild PIA, and $58.5 billion/$2.2 billion for opioid use with moderate/severe PIA.Limitations: Unobservable/unmeasured factors that could not be accounted for.Conclusions: Opioid use with moderate/severe PIA had significantly higher HRU, costs, and wage loss; opioid use was more relevant than PIA to the economic burden. These results suggest unmet needs for alternative pain management strategies.