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Background Recent mpox outbreaks have documented the spread of clade Ib beyond the Central Africa, where it was historically confined. However, data describing the clinical and virological features of clade Ib infections in Europe remain limited.Materials and Methods We conducted a descriptive analysis of patients presenting with suspected mpox to the STI outpatient clinic of Luigi Sacco Hospital (Milan, Italy) between 1 January and 1 February 2026. Infection was confirmed by real-time polymerase chain reaction (RT-PCR) on skin lesion, blood, anal, and oropharyngeal swabs. Viral clade was determined by whole-genome sequencing. Demographic, clinical, and laboratory data were collected at diagnosis and during follow-up. Cycle threshold (CT) values were used as a surrogate marker of viral load.Results Six male patients were diagnosed with mpox clade Ib. Median age was 38 years. One patient was living with HIV; among the five HIV-negative individuals, three reported on-demand HIV pre-exposure prophylaxis use. One patient had previously received two doses of mpox vaccine. A recent at-risk sexual exposure preceding symptom onset was reported in four cases.Median CT values were 17.5 for skin lesions, 20 for oropharyngeal swabs, 29.5 for anal swabs, and 33 for blood samples, suggesting higher viral loads in mucocutaneous sites.All patients presented with predominant cutaneous involvement, including pustular and ulcerative lesions. Facial lesions were observed in all cases, while truncal and/or acral involvement occurred in five. Anorectal involvement was documented in three patients and was associated with severe pain; one also reported rectal bleeding. Systemic symptoms included fever (n=4), lymphadenopathy (n=4), pharyngodynia (n=4), and myalgia (n=3). Sexually transmitted coinfections were identified in two patients (HSV-2 proctitis and anal Mycoplasma genitalium infection).One patient required hospitalization. Tecovirimat was administered in three patients, leading to rapid improvement of painful symptoms within four days; lesions progressed to crusting over subsequent weeks. No drug-related adverse events were observed. Complications included one facial methicillin-resistant Staphylococcus aureus skin infection and one case of deep, non-epithelialized genital ulcers.Conclusions This cluster provides an early characterization of clade Ib mpox in Milan, and underscores the importance of clinical awareness among healthcare workers. High viral loads in skin and oropharyngeal samples, and their potential implications in transmission, underscore the importance of early recognition to facilitate timely diagnosis, appropriate clinical management, and containment as clade Ib continues to emerge in Europe.