To determine whether there is a causal effect of oral contraceptive (OC) treatment on general well-being and depressed mood in healthy women. Double-blind, randomized, and placebo-controlled trial. University hospital. Three hundred and forty healthy women aged 18-35 years randomized to treatment, of whom 332 completed the data collection at follow-up evaluation. A combined OC (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo for 3 months of treatment. Primary outcome measures: global score of Psychological General Well-Being Index (PGWBI) and the Beck Depression Inventory (BDI); secondary outcome measures: six separate dimensions of the PGWBI. The OC treatment statistically significantly decreased general well-being compared with placebo -4.12 (95% CI, -7.18 to -1.06). Furthermore, OC decreased the following PGWBI dimensions compared with placebo: positive well-being -3.90 (95% CI, -7.78 to -0.01), self-control -6.63 (95% CI, -11.20 to -2.06), and vitality -6.84 (95% CI, -10.80 to -2.88). The effect of OC on depressive symptoms and on the PGWBI dimension depressed mood were not statistically significant. This study demonstrates a statistically significant reduction in general well-being by a first-choice OC in comparison with placebo in healthy women. We found no statistically significant effects on depressive symptoms. A reduction in general well-being should be of clinical importance.