Acyclovir is known for its antiviral activity against some pathogenic viruses such as the Epstein-Barr virus (EBV) that causes infectious mononucleosis (IM) and IM-like illness. Therefore, we empirically administered acyclovir to patients with suspected EBV-IM and IM like-illness, upon their admission to our hospital. We admitted 25 patients, who were hospitalized for fever and lymphadenopathy, to the Tohoku University Hospital Infectious Disease Ward. As part of treatment, 8 of these patients were given acyclovir (750 mg/day) with their consent and were assigned to the acyclovir group; the remaining 17 patients were assigned to the control group. The mean age of acyclovir patients (all men) was 42 ± 5.2 years, and that of control patients (13 men and 4 women) was 31 ± 3.0 years. The cause of illness was confirmed as EBV-IM in 6 patients (1, acyclovir; 5, control), and remained unknown for the other 19 IM-like illness patients (7, acyclovir; 12, control). A shorter duration of hospitalization and fever was observed in the acyclovir compared to that in the control patients (hospitalization duration: 16 ± 3.7 vs. 27 ± 7.7 days, P = 0.36; fever duration: 4.5 ± 1.8 vs. 18 ± 6.5 days, P = 0.04). Additionally, serum amyloid A (SAA) levels were lower in acyclovir than that in control patients (98 ± 37 vs. 505 ± 204 μg/mL, P = 0.02). Therefore, we propose that acyclovir is a potential therapeutic agent for both EBV-IM and IM like-illnesses. Future studies should further examine its mechanism of action.