Background Since May 2022, a new outbreak of monkeypox has been reported in several countries, including Spain. The clinical and epidemiological characteristics of the cases in this outbreak may differ from those in earlier reports. Objectives To document the clinical and epidemiological characteristics of cases of monkeypox in the current outbreak. Methods We conducted a prospective cross‐sectional study in multiple medical facilities in Spain to describe the cases of monkeypox in the 2022 outbreak. Results In total, 185 patients were included. Most cases started with primarily localized homogeneous papules, not pustules, in the probable area of inoculation, which could be cutaneous or mucous, including single lesions. Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common lesions included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Four patients were hospitalized, none died. Smallpox vaccination and well‐controlled HIV disease were not associated with markers of severity. Contact during sex is the most likely mechanism of transmission. In this outbreak, cases have been described in men who have sex with men and are strongly associated with high‐risk sexual behaviours. Seventy‐six per cent of the patients had other sexually transmitted diseases upon screening. Conclusions The clinical findings in this outbreak differ from previous findings and highly suggest contact transmission and initiation at the entry site. The characterization of the epidemiology of this outbreak has implications for control. What is already known about this topic? Monkeypox eruption is described as consisting of pustules. The roles of HIV and previous smallpox vaccination in the prognosis are unknown. The transmission route was initially described as respiratory droplets and was later suggested to be via sexual contact. What does this study add? Initial lesions at the probable inoculation area were homogeneous and papular (pseudopustules). Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common signs included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Well‐controlled HIV and previous smallpox vaccination were not associated with severity. No patient died. The data support the hypothesis of transmission via contact during sex. Although this might change, the outbreak is currently limited mostly to men who have sex with men, with high‐risk factors for sexually transmitted diseases.

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