Tramadol is a centrally acting, synthetic analgesic. Its mechanism of action involves weak binding to the mu-opioid receptors and inhibition of reuptake of both norepinephrine and serotonin. It has been used to treat moderate-to-severe pain for 30 years in Europe and more than 10 years in the USA. Initially available in immediate-release form (dosing four- to six-times daily), in recent years, a variety of once-daily formulations have been developed utilizing different extended-release technologies, which provide different pharmacokinetic characteristics (time to reach therapeutic plasma levels, time to steady state and plasma levels at 24 h), leading to different clinical implications (e.g., titration schedule, time to onset and adverse events). This review addresses the efficacy and safety of the four marketed once-daily formulations with published data in studies on osteoarthritis. Analgesic efficacy and safety results from double-blind clinical studies utilizing 100-400 mg daily doses of these once-daily formulations have been published. Most subjects took tramadol 200 or 300 mg/day. Each once-daily formulation demonstrated statistically superior efficacy compared with placebo or similar efficacy to immediate-release or twice-daily tramadol. Availability of short- and long-term safety data varies among the formulations. Generally, adverse events are typical of tramadol (constipation, nausea, dizziness and somnolence). Descriptively, a trend to comparable or lower incidence and severity of adverse events seems apparent with the various once-daily formulations. Tramadol once-daily formulations are more effective than placebo and at least as effective and well tolerated as immediate-release formulations in the treatment of pain due to osteoarthritis, and offer a reduced dosing regimen, which is especially valuable in elderly patients.