This study aims to quantify clinical and economic burden of rotavirus (RV) infection pre- and post-vaccine introduction in commercially insured and Medicaid populations. Beneficiaries with continuous enrollment for ≥6 months while <5 years of age were identified separately in commercial (2000–2010) and Medicaid (2002–2009) claims databases. Commercial and Medicaid databases included 3 998 708 and 1 034 440 eligible children, respectively, observed from enrollment start date(s) to end of eligibility or 5-years-old. Rates of RV-coded and diarrhea-coded encounters and first RV episodes, and incremental cost of first RV episodes were calculated. In the post-vaccine period, rates per 10 000 person-years for RV-coded hospitalizations, outpatient visits and ER visits were 5.58 (95% CI, 5.37–5.80), 6.96 (95% CI, 6.75–7.20), and 4.85 (95% CI, 4.66–5.06), respectively (pre-vaccine, 16.67 [95% CI, 16.19–17.15], 13.20 [95% CI, 12.78–13.63], 11.26 [95% CI, 10.87–11.66], respectively), for commercially insured. In Medicaid the corresponding rates were 10.53 (95% CI, 9.60–11.56), 11.72 (95% CI, 10.73–12.80), and 9.11 (95% CI, 8.24–10.07) (pre-vaccine, 19.78 [95% CI, 19.14–20.45], 19.39 [95% CI, 18.75–20.05], 27.61 [95% CI, 26.84–28.40]). Incidence rate per 10 000 person-years for first RV episode pre- vs. post-vaccine were 27.03 (95% CI, 26.42–27.65) vs. 10.14 (95% CI, 9.86–10.44) in the commercially insured population and 37.71 (95% CI, 36.81–38.63) vs. 18.64 (95% CI, 17.37–19.99) in Medicaid. Incremental per-patient per-month cost of first RV episode was $3363 (95% CI, $3308-$3418) among commercially insured and $1831 (95% CI, $1768-$1887) in Medicaid. Since vaccine introduction clinical burden of RV disease decreased among children; costs associated with RV episodes remained significant across insured populations.