Abstract: This post hoc study used data from the naturalistic Schizophrenia Outpatient Health Outcomes study, assessing the factors associated with starting antipsychotic monotherapy and the annual rate and duration of antipsychotic monotherapy among patients initiating atypical antipsychotics (N = 6866). Descriptive and regression analyses were used. Factors associated with starting antipsychotic monotherapy at baseline were antipsychotic treatment for the first time, shorter duration of illness, less severe illness, and better social functioning. Baseline monotherapy was maintained throughout 12 months by 63.2% of patients and was significantly greater for olanzapine (66.8%) than for risperidone (62.8%), quetiapine (43.4%), or amisulpride (52.6%) (all p ≤ 0.01). The predicted mean number of days on baseline monotherapy was significantly longer for olanzapine than for risperidone, quetiapine, or amisulpride (all p < 0.01). Initiation of antipsychotic monotherapy at baseline is associated with select baseline patient characteristics. Olanzapine was found to have the highest monotherapy rate and the longest duration of maintained monotherapy, followed by risperidone, amisulpride, and quetiapine.