OBJECTIVE: To evaluate the comparative effectiveness of nonbiologic disease-modifying antirheumatic drugs (DMARD) versus biologic DMARD (bDMARD) for treatment of rheumatoid arthritis (RA), using 2 common analytic approaches. METHODS: We analyzed change in Clinical Disease Activity Index (CDAI) scores in patients with RA enrolled in a US-based observational registry from 2001 to 2008 using multivariable (MV) regression and propensity score (PS) matching. Among patients who initiated treatment with a nonbiologic DMARD (n = 1729), we compared patients who switched to, or added, another nonbiologic (n = 182) or a bDMARD (n = 342) at 5, 9, and 24 months after treatment change. RESULTS: Both analytic approaches showed that patients switching to or adding another nonbiologic DMARD demonstrated improvement across 9 and 24 months (both p < 0.001). Both approaches also demonstrated greater improvement in CDAI among recipients of bDMARD relative to a second nonbiologic DMARD at 5 months (p < 0.02). The MV regression approach upheld these results at 9 and 24 months (p < 0.03). In contrast, the PS-matching approach did not show a sustained advantage with bDMARD at these later timepoints, possibly because of lower statistical power and/or lower baseline disease activity in the PS-matched cohort. CONCLUSION: Patients in both treatment groups generally experienced lower CDAI scores across time. Patients switching to bDMARD demonstrated greater improvement than patients switching to nonbiologic DMARD with both analytic approaches at 5 months. Relative advantages with bDMARD were observed at 9 and 24 months only with MV regression. These analyses provide a practical example of how findings in comparative effectiveness research can diverge with different methodological approaches.