Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain.