Organizational downsizing may be a risk factor for morbidity among both the displaced and those who remain in work. However, the knowledge is limited regarding its impact on clinically relevant mental health problems. Our objective was to investigate purchases of prescription antidepressants across 5 years in relation to workplace downsizing. We studied all Swedish residents 2004 throughout 2010, 22-54 years old in 2006, gainfully employed, and with a stable labor market position up to 2006. People primarily employed at a workplace with ≥18% staff reduction were considered exposed to major downsizing (in 2006-2007, 2007-2008, or 2008-2009). We applied repeated measures regression analyses through generalized estimating equations, calculating odds of any purchase of prescription antidepressants (inferred from the prescribed drug register) within five 12-month periods from 2 years before to 2 years after the period of major downsizing and compared the trends for newly exposed (n = 632,500) and unexposed (n = 1,021,759) to major downsizing. The odds of purchasing prescription antidepressants for exposed increased more than for nonexposed, mainly peridownsizing (1 year before to 1 year after), and postdownsizing (1 year after to 2 years after) for survivors (odds ratio 1.24 vs. 1.14 peridownsizing and 1.12 vs. 1.00 postdownsizing) and those changing workplace (odds ratio 1.22 vs. 1.14 peridownsizing and 1.10 vs. 1.00 postdownsizing) with no previous sickness absence or disability pension (≥7% more than unexposed peri- and postdownsizing). This large-scale study indicates that downsizing is associated with a slight increase in the odds of purchasing prescription antidepressants among people without previous sickness absence or disability pension.