Monkeypox is a previously rare viral zoonosis affecting predominantly the African continent. Since May 2022, an increasing number of cases with no known epidemiologic link to Africa have been reported for the first time in the rest of the world. We described the epidemiologic and clinical characteristics of all patients attended at our center until August 9 with a confirmed diagnosis of monkeypox. Forty-nine patients were included. The mean age was 37.6 years. Ninety-eight percent of patients were male, 96% were men who have sex with men, and 4% were heterosexual. Thirty-one percent of patients had a history of human immunodeficiency virus infection. Ninety-six percent of patients declared a unprotected sexual relationship before the onset of symptoms, and 41% had a history of recent travel. Ninety-eight percent of patients presented with cutaneous involvement affecting the genital (59%), perianal (41%), and perioral (35%) regions. Systemic symptoms were present in 80% of the patients and included lymphadenopathies (71%), asthenia (65%), fever (65%), headache (37%), arthromyalgias (45%), pharyngitis (35%), proctitis (29%), and dysuria (6%). Coinfection by other sexually transmitted infections was detected in 20% of patients. The sensitivity values of polymerase chain reaction test for monkeypox in urethral, anal, and oropharyngeal exudates analyzed were 88%, 79%, and 68%, respectively. Complications included a myopericarditis that represented the only hospitalized patient, edema (8%) and bacterial superinfection (4%). No deaths were reported. The findings of this case series support the sexual contact as the main route of transmission of the disease and highlight some atypical clinical presentations not described in endemic cases.