Context: Dealing with young girls with primary amenorrhea is a frequent situation in Pediatric and Adolescent Gynecology. However, it is rather rare to discover pathology afflicting both ovaries and genital tract. Objective: In this case report we present two interesting cases of adolescent girls with primary amenorrhea, who raised a differential diagnosis challenge to our specialists. Clinical presentation – Intervention: The first patient visited our office at the age of 18 years in order to investigate primary amenorrhea. Patient had nil past medical and family history. Clinical examination revealed breast development at Tanner stage 3 and pubic hair at Tanner stage 4. She had a 46XX karyotype with high gonadotrophin levels FSH=74,52mIU/L, LH=15,49 mIU/L and low estogens E2=5.0 pg/mL. Uterus and ovaries appeared hypoplastic on ultrasound check; endometrial lining was thin. Bone densiometry showed osteopenia, which confirmed her low estrogen status. Hormone replacement therapy was initiated, including tablets, trandermal patches and gels; however neither of the regimens achieved withdrawal bleeding, despite the presence of endometrial cells with estrogen and progesterone receptors. Concurrently, bone density, pap smear maturation index was responsive to estrogens. To our surprise, on a recent MRI endometrial thickness was measured 11mm and a hysteroscopy was scheduled. Our findings were an aplastic endometrial cavity with no apparent fallopian ostia. In this case the patient’s ovarian insufficiency is complicated by unresponsive endometrium. The second patient was a 16 year old girl with primary amenorrhea and hearing impairment, who at first clinical presentation had a Tanner 5 breast development and Tanner 4 pubic hair. Blood results showed hypergonadotrophic hypogonadism and a 46XX karyotype. Additionally, clinical examination revealed a blind pouch instead of a vagina and during rectal exam, there was no palpable uterus. Imaging and laparoscopy findings showed rudimentary uterine horns and hypoplastic ovaries, which led to a diagnosis of concurrent Mayer-Rokitansky- Kuster-Hauser syndrome and premature ovarian insufficiency. Conclusions: Following the diagnostic algorithm of primary amenorrhea can sometimes lead to unpredictable results. Coincidence of a congenital anomaly of genital tract and ovarian insufficiency in patients with normal 46XX karyotype is rarely observed and scarce in literature.