Background <p>We evaluated the potential association between depressive symptoms and work productivity loss among employed individuals with schizophrenia.</p> Methods <p>This was a 48-week, prospective, longitudinal, web-based, observational questionnaire study. Patients with schizophrenia, aged 20–59 years, who were employed or on sick leave were included. The Patient Health Questionnaire-9 (PHQ-9), Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), Health Utilities Index Mark 3 (HUI3), and Japanese version of the Pittsburgh Sleep Quality Index (PSQI) were used to assess depressive symptom severity, work productivity loss, quality of life, and sleep disturbance, respectively.</p> Results <p>Of the 107 patients included, the mean age was 40.9 years, 57.0% were full-time workers, and 47.7% had depressive symptoms based on a PHQ-9 score ≥ 10. Regarding the primary endpoint, there was a weak but significant correlation between change from baseline to 48 weeks in depressive symptoms and presenteeism (WPAI-GH) (Pearson <i>R</i> = 0.308, <i>P</i> = 0.013). No significant correlation was observed between sleep disturbance (PSQI) and presenteeism or between cognitive impairment (HUI3 cognition) and presenteeism. Multiple regression analysis revealed that the change in depressive symptoms from baseline to 48 weeks significantly contributed to presenteeism (regression coefficient = 1.932 [95% confidence interval 0.182–3.682], <i>P</i> = 0.031). Cluster analysis identified two clusters and showed that patients with higher presenteeism throughout the study period had greater depression severity at baseline.</p> Conclusions <p>Changes in depressive symptoms were modestly associated with changes in presenteeism among employed individuals with schizophrenia.</p> Trial registration <p>UMIN Clinical Trials Registry (UMIN000050711): Registration date, 29 March 2023).</p>