Background: It has been hypothesised that oral oestrogen replacement therapy may increase levels of C-reactive protein (CRP), a marker of inflammation associated with increased risk of future cardiovascular events. However, it is possible that intranasal oestrogen replacement therapy have different effects on serum CRP levels. Aim: To investigate the effect of postmenopausal intranasal oestrogen replacement therapy on serum levels of CRP. A prospective comparative study was carried out. Methods: Twenty-nine healthy hysterectomised, postmenopausal women received 300 μg/day of intranasal 17β-oestradiol (E2). The serum levels of CRP after 3 and 6 months after starting treatment were compared with baseline values. Results: There were no significant changes in the values of CRP after 3 and 6 months of treatment (P = 0.305, P = 0. 149, respectively). Conclusions: The data from the present study suggest that intranasal administration of E2 does not affect CRP levels, possibly by avoiding a hepatic first-pass effect. The possible cardiovascular protective role of intranasal oestrogen might be related to its effect of not increasing CRP levels.