BackgroundCyclophosphamide (CP) is used extensively as a chemotherapeutic and an immunosuppressive agent during organ transplantation. However, its clinical utility is limited by adverse actions on the human reproductive system. Melatonin is detected in the human and animal reproductive system, hence assumed to play a useful role in the reproductive cells. Aim of workTo examine the effect of melatonin on the histological and immunohistochemical changes that appear in the cells of the testes of albino rats treated with CP. Materials and methodsForty-two adult male albino rats were classified into group I (control), subgroups IIa and IIIa (CP by an intraperitoneal injection for 2 and 5 weeks, respectively), subgroups IIb and IIIb (CP and melatonin by an intraperitoneal injection for 2 and 5 weeks, respectively), and subgroups IIc and IIIc (CP for 2 and 5 weeks and left for 2 and 5 weeks for recovery, respectively). The rats were weighed, sacrificed, and the right testes were weighed and processed for paraffin sections. A histological study was carried out using H&E and Masson's trichrome. Immunohistochemical study using the BCL2 antiapoptotic onchoprotein and a morphometric study were carried out. Results A significant decrease was found in the mean body weight in subgroups IIa, IIIa, and IIIc and in the mean testicular weight in group III. There were distortions in some seminiferous tubules, degeneration of spermatogenic cells, perivascular and intertubular fibrosis, and negative immunoexpression of BCL2. These changes were more marked in group III than in group II. The use of melatonin in subgroups (IIb, IIIb) conferred partial protection against all of the above-mentioned changes. ConclusionProlonged administration of CP to rats can induce testicular lesions. Withdrawal of the drug does not ameliorate this effect. The concomitant administration of melatonin with CP led to a partial improvement in testicular lesions induced by CP.