Abstract Background Mood disorders, with a particular emphasis on depression, exert a significant influence on job performance and participation, leading to substantial levels of workforce presenteeism and absenteeism. Often, individuals who rejoin the workforce following a depression-induced sick leave encounter lingering impairments and are frequently prone to repeated periods of absence. Therefore, predicting occupational engagement in a timely manner is crucial for devising appropriate management strategies for individuals affected by depression. Nonetheless, there is a lack of clear indicators in patients with depression to predict continuous employment. Aims & Objectives The primary objective of the present study is to investigate the association between illness severity, as measured by the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS- SR), and absenteeism among workers with mood disorders. Furthermore, we aimed to propose a clinically relevant cut-off score for this scale to predict potential unemployment or sick leave in this population. Methods In a prospective observational trial conducted in Tokyo, 112 outpatients diagnosed with either major depressive disorder or bipolar depression were enrolled. Their employment statuses of these participants were tracked over a six-month period after their QIDS-SR scores were recorded. Based on their employment trajectories, participants were categorized into either continuous or non-continuous employment groups. Binary logistic regression was applied to examine the relationship between the QIDS-SR scores and employment outcomes, with adjustments for age, gender, and psychiatric diagnoses. Receiver operating characteristic curves were utilized to identify the optimal QIDS-SR cut-off values for predicting continuous employment. Results A total of 112 patients, with an average age of 44.4±10.8 years, participated in the present study. Of the 112 patients, 76 were diagnosed with depression, 36 with bipolar disorder, and 69 were prescribed antidepressants. 62 participants were continuously employed during the follow-up period, while the remaining 50 were classified into the non-continuous employment group. The mean QIDS-SR score at baseline was 7.6±4.7 and 11.5±5.5 for the continuous and non-continuous employment groups, respectively. There was no significant difference observed in the demographic characteristics between the two groups, except for the QIDS-SR score. In the binary logistic regression model, a lower score on the QIDS-SR was linked to an elevated likelihood of continuous employment, presenting adjusted an odds ratio of 1.15 (95% confidence interval (CI): 1.06-1.27, p = 0.001), Variables including age, gender, and psychiatric diagnosis were not found to correlate with continuous employment. The AUC value for identifying continuous employment was 0.72 (95% Cl: 0.62-0.82), indicating acceptable accuracy. By using the Youden Index, the optimal cut-off point for identifying continuous employment was determined as a score of 10/11. Applying this cut-off yielded sensitivity and specificity values of 63% and 71%, respectively. Discussion & Conclusion The results emphasize the potential of the QIDS-SR as a prognostic instrument for predicting employment outcomes among individuals with depressive disorders. These findings further underscore the importance of managing depressive symptoms to mild or lower intensities to ensure ongoing employment.