Objective. To assess the efficacy and safety of combination pain therapy for people with inflammatory arthritis (IA). Methods. Systematic review of randomized controlled trials using Cochrane Collaboration methodology. Combination therapy was defined as at least 2 drugs from the following classes: analgesics, non-steroidal antiinflammatory drugs (NSAID), opioids, opioid-like drugs, and neuromodulators (antidepressants, anticonvulsants, and muscle relaxants). The main efficacy and safety outcomes were pain and withdrawals due to adverse events, respectively. Results. Twenty-three trials (total of 912 patients) met inclusion criteria [22 in rheumatoid arthritis (RA) and 1 in a mixed population of RA and osteoarthritis]. All except 1 were published before 1990. All trials were at high risk of bias, and heterogeneity precluded metaanalysis. Statistically significant differences between treatment groups were reported in only 5/23 (22 ) trials: in 3 trials combination therapy was better (2 trials with NSAID + analgesic versus NSAID only and 1 trial with 2 NSAID versus 1 NSAID), in 1 trial combination therapy was worse (opioid + neuromodulator versus opioid only), and in the fifth trial (NSAID + analgesic versus NSAID alone) reported results were mixed depending on the dosage used in the monotherapy arm. In general, there were no differences in safety and withdrawals due to inadequate analgesia between combination and monotherapy. Conclusion. Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for pain management in IA. Well-designed trials are needed to address this question.