Paroxetine (a selective serotonin reuptake inhibitor) was successfully labeled with 125I via direct electrophilic substitution reaction at ambient temperature. The reaction parameters studied were paroxetine amount, CAT amount, pH of the reaction mixture, reaction temperature, reaction time and in vitro stability of 125I-paroxetine. 125I-paroxetine was obtained with a maximum labeling yield of 94 ± 0.23% and in vitro stability up to 24 h. Biodistribution studies showed that maximum in vivo uptake of 125I-paroxetine in lungs was 27.89 ± 1.03% injected activity/g tissue at 15 min post-injection and retention in lungs remained high up to 1 h, whereas the clearance from mice appeared to proceed mainly via the hepatobiliary pathway. 125I-paroxetine is not a blood product and so it is more safe than the currently available 99mTc-macroaggregated albumin (99mTc-MAA), and its lung uptake is higher than that of the recently discovered 99mTc(CO)5I and 99mTc-DHPM. As a conclusion, radioiodinated paroxetine could be used as a novel radiopharmaceutical for lung perfusion scan safer than the currently available 99mTc-MAA and more potential than the recently discovered 99mTc(CO)5I and 99mTc-DHPM.