Although early initiation of disease-modifying antirheumatic drugs (DMARDs) is effective in controlling short-term joint damage in individuals with rheumatoid arthritis (RA), the long-term benefit in disease progression is still controversial. We examined the long-term benefit of early DMARD initiation on radiographic progression in early RA. We identified published and unpublished clinical trials and observational studies from 1966 to September 2004 examining the association between delay to treatment initiation and progressive radiographic joint damage. We included studies of persons with RA disease duration <2 years and DMARD therapy of similar efficacy during followup. The differences in annual rates of radiographic progression between early and delayed therapy were pooled as standardized mean differences (SMDs). A total of 12 studies met the inclusion criteria. The pooled estimate of effects from these studies demonstrated a significant reduction of radiographic progression in patients treated early (-0.19 SMD, 95% confidence interval [95% CI] -0.34, -0.04), which corresponded to a -33% reduction (95% CI -50, -16) in long-term progression rates compared with patients treated later. Patients with more aggressive disease seemed to benefit most from early DMARD initiation (P = 0.04). These results support the existence of a critical period to initiate antirheumatic therapy, a therapeutic window of opportunity early in the course of RA associated with sustained benefit in radiographic progression for up to 5 years. Prompt initiation of antirheumatic therapy in persons with RA may alter the long-term course of the disease.