OBJECTIVE: We examined the relationship of increasing prescription volume of newer antidepressants, introduced in Japan in 1999, to national rates of suicide. METHOD: The relationship between annual changes in rates of suicide (obtained from the Japanese Ministry of Health, Labor, and Welfare Vital Statistics Database) and prescription volume of the newer antidepressants paroxetine, fluvoxamine, and milnacipran (obtained from the database of IMS Japan K.K.), stratified by gender and age groups, was modeled statistically for the years 1999 through 2003. Effects of unemployment and alcohol consumption and the interaction of gender and age with antidepressant prescribing were assessed. RESULTS: From 1999 through 2003 in Japan, total antidepressant prescriptions increased 57% among males and 50% among females. Approximately 80% of this increase involved the selective serotonin reuptake inhibitors (SSRIs). To reduce a limitation of ecological analysis, we compared annual change in prescription and suicide rates, which eliminates the effect of long-term (secular) linear trends. We found an inverse association between year-to-year changes in the suicide rate and prescription volume of newer antidepressants (fluvoxamine, paroxetine, and milnacipran) (beta = -1.34, p = .008) and SSRIs specifically (fluvoxamine, paroxetine) (beta = -1.41, p = .019). An increase of 1 defined daily dose of SSRI use/1000 population/day was associated with a 6% decrease in suicide rate. Exploratory analysis suggested a stronger association in males, who experienced a greater increase in antidepressant use. Changes in unemployment and alcohol consumption rates did not explain the association. CONCLUSION: In Japan during 1999 through 2003, absent long-term linear trend effects, annual increases in prescribing of newer antidepressant medications, mainly SSRIs, were associated with annual decreases in suicide rates, particularly among males.