Background <p>The major type of breast cancer in males is the estrogen receptor-positive breast cancer, and can be managed with antiestrogenic hormonal compounds that have been reported to impair sexual functions in males. The commonest of these antiestrogenic agents is tamoxifen (TAM), which has also been shown to impair erectile function. Omega-3 fatty acids (O3FA), on the other hand, are an antioxidant obtained from diets, and they possess fertility-enhancing properties. In light of these, we considered the effect of O3FA on TAM-induced alterations in penile erectile response in male Wistar rats.</p> Method <p>Sixty (60) male Wistar rats were randomized into four oral treatment groups (15 animals/group): control, O3FA (300&#xa0;mg/kg), TAM (0.4&#xa0;mg/kg), and TAM+O3FA treatment group. Male rats were placed in transparent cages under dim light, paired with hormonally primed receptive females, and sexual behavior was assessed before biochemical analysis.</p> Results <p>TAM significantly disrupted male penile erectile reflexes and motivation to mate and decreased dopamine with the concomitant increase in serotonin, monoamine oxidase, arginase, and phosphodiesterase-5. These events were accompanied by a significant decrease in nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Also, TAM exposure altered antioxidant status (evidenced by a significant increase in penile MDA and decrease in Nrf2, SOD, CAT, GSH, and GPx), leading to penile inflammatory response (increased IL-1β, TnF-α, MPO, Nf-κb, XO, and UA) and caspase-3-mediated apoptosis. However, O3FA co-treatment attenuated TAM-induced alterations in penile erectile response and boosted the NO-mediated signaling and antioxidant status.</p> Conclusion <p>Based on these results, TAM administration in healthy rats was associated with increased penile oxidative stress, while O3FA attenuated some of these changes.</p> Clinical trial number <p>Not applicable.</p>