Background: We performed an epidemiologic study to analyze nationwide time trends in adult psychotropic drug use over a period from 2006 to 2012, and to identify those factors associated with the likelihood of consumption of these drugs during the study period; Methods: Cross-sectional study on psychotropic medication in the Spanish adult population. We used secondary individualized data drawn from the 2006 and 2012 Spanish National Health Surveys (SNHS). The dependent variable was the use of psychotropic drugs in the previous two weeks. Independent variables included socio-demographic characteristics, comorbidity, lifestyles and healthcare resource utilization. Using logistic multivariate regression models, we analyzed the temporal evolution of psychotropic medication consumption between 2006 and 2012 in both sexes; Results: The prevalence of psychotropic drug use was significantly greater in women (18.14% vs. 8.08% in 2012 (p < 0.05). In Spanish women, the variables associated with a greater probability of psychotropic use were, age, unemployment (adjusted odds ratio (AOR), 1.60; 95% CI, 1.24–2.07), negative perception of health or taking non-psychotropic drugs. Among men, psychotropic use is associated with presence of chronic disease, negative perception of health (AOR, 3.27; 95% CI, 2.62–4.07 in 2012) or inactive status; Conclusions: Between 2006 and 2012, the probability of having taken psychotropic drugs increased by 16% among women. Unemployed women aged ≥45 years with a negative perception of their health constitute a clear risk profile in terms of psychotropic drug use. Inactive men who have a negative perception of their health are the group most likely to consume psychotropic drugs.