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.