Fluoxetine (FLX) has a unique pharmacokinetic profile. Its major metabolite, norfluoxetine (NFLX), possesses FLX's antidepressant efficacy and a half-life of 7 to 15 days, suggesting the possibility of nonstandard dosing strategies. This study examined the tolerability of a weekly dose and its equivalence to daily dosing of FLX for the continuation phase of treatment for major depressive disorder (MDD). One hundred fourteen subjects initially received open-label treatment with 20 mg of FLX daily for 7 weeks. Subsequently, 70 subjects with a score on the Hamilton Rating Scale for Depression (HAM-D) of 12 or less were randomly assigned in a double-blind design to one of three treatment groups: 20 mg FLX daily (N = 21), 60 mg FLX weekly (N = 28), or placebo (N = 21) and were followed for 7 weeks. HAM-D scores and blood levels of FLX and NFLX were analyzed using a repeated-measures analysis of variance. During the double-blind phase, blood levels for both FLX and NFLX differed across the treatment groups, yet no statistically significant difference in HAM-D scores was observed. There was no difference in the dropout rate across the groups. Subjects could not correctly identify the treatment group into which they were assigned. Weekly dosing of FLX seems to be well tolerated and possibly as effective as daily dosing in maintaining the therapeutic response in subjects with MDD.