Background: Depression is common in the primary care setting and tobacco use is more prevalent among individuals with depression. Recent research has linked smoking to poorer outcomes of depression treatment. We hypothesized that in adult primary care patients with the diagnosis of depression, current smoking would have a negative impact on clinical outcomes, regardless of treatment type (usual primary care [UC] vs collaborative care management [CCM]). Methods: A retrospective chart review study of 5155 adult primary care patients with depression in a primary care practice in southeast Minnesota was completed. Variables obtained included age, gender, marital status, race, smoking status, initial Patient Health Questionnaire–9 (PHQ-9), and 6-month PHQ-9. Clinical remission (CR) was defined as 6-month PHQ-9 <5. Persistent depressive symptoms (PDS) were defined as PHQ-9 ≥10 at 6 months. Treatment in both CCM and UC were compared. Results: Using intention to treat analysis, depressed smokers treated with CCM were 4.60 times as likely (95% CI 3.24-6.52, P < .001) to reach CR and were significantly less likely to have PDS at 6 months (adjusted odds ratio [AOR] 0.19, 95% CI 0.14-0.25, P < .001) compared with smokers in UC. After a 6-month follow-up, depressed smokers treated with CCM were 1.75 times as likely (95% CI 1.18-2.59, P = .006) to reach CR and were significantly less likely to have PDS (AOR 0.45, 95% CI 0.31-0.64, P < .001) compared with smokers in UC. Conclusions: CCM significantly improved depression outcomes for smokers at 6 months compared with UC. However, in the UC group, smoking outcomes were not statistically different at 6 months for either remission or PDS. Also, nonsmokers in CCM had the best clinical outcomes at 6 months in both achieving clinical remission and reduction of PDS when compared with smokers in UC as the reference group.