Five patients with vital, unruptured interstitial pregnancies of less than 3 cm maximum diameter were treated successfully with methotrexate and leucovorin rescue. Four pregnancies showed cardiac activity. Diagnosis was established with transvaginal ultrasonography in all patients. The human chorionic gonadotrophin serum levels were measured to monitor the effectiveness of therapy. This is the first publication on methotrexate treatment for interstitial twin pregnancy and the first on instillation of methotrexate after puncture and aspiration of interstitial pregnancy. In all cases, total and uneventful regression of trophoblast tissue was achieved. No adverse reactions were observed. The advantages and drawbacks of these therapeutic approaches are discussed. Methotrexate appears to be an effective medical non-surgical treatment for unruptured interstitial pregnancy with or without cardiac activity, and preserves reproductive potential.