Estrogens may affect the essential n-6 and n-3 fatty acids arachidonic acid (AA; C20:4n-6) and docosahexaenoic acid (DHA; C22:6n-3). Therefore, we investigated the long-term effects of hormone replacement therapy and raloxifene, a selective estrogen-receptor modulator, in two randomized, double-blind, placebo-controlled studies. In study I, 95 healthy, non-hysterectomized, early postmenopausal women (age range 47-59 years) received one of the following treatments: daily raloxifene 60 mg (n=24), daily raloxifene 150 mg (n=23), 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA; n=24), or placebo (n=24). In study II, 30 men (age range 60-69 years) received daily 120 mg raloxifene (n=15) or placebo (n=15). In study I, plasma cholesteryl ester fatty acids were measured at baseline and after 6, 12, and 24 months in 83 (drop out rate 13%), 73 (23%), and 70 (25%) women respectively. In study II, fatty acids were measured at baseline and after 3 months in 29 men (drop out rate 3%). In postmenopausal women, administration of 150 mg raloxifene increased AA by a mean of +6.1% (P=0.055, not significant). Administration of CEE plus MPA increased AA by +14.1% (P<0.0005). Mean changes in DHA were +22.1% (P=0.003) and +14.9% (P=0.047) respectively, as compared with placebo. In men, 120 mg raloxifene for 3 months did not significantly affect AA (-5.2%; P=0.342) or DHA (+4.0%; P=0.755), but it increased testosterone levels by +19.8% (P=0.006). Administration of raloxifene 150 mg/day as well as CEE plus MPA to postmenopausal women increases the proportion of AA and DHA in plasma cholesteryl esters during a follow-up of 2 years. Short term administration of raloxifene in elderly men did not affect AA or DHA. The synthesis of AA and DHA from precursors may be enhanced through an estrogen receptor-dependent pathway.