BACKGROUND: Mpox, caused by the monkeypox virus, is a serious public health threat in Africa, especially in DR Congo. Previously limited to endemic areas with clade 1a, monkeypox virus has recently spread to non-endemic regions, where clade 1b has emerged. This study provides a clinical comparison of mpox cases in DR Congo regions where clade 1a and clade 1b are prevalent. METHODS: We conducted a retrospective observational study, analysing PCR-confirmed mpox cases reported from sentinel health zones in seven provinces between Oct 1, 2023, and Sept 31, 2024. Cases from the newly affected provinces (South-Kivu and Kinshasa) were described along with those from four endemic provinces (Mai-Ndombe, Tshuapa, Tshopo, South-Ubangi, and Équateur). Surveillance data, including type of exposure, demographic details, clinical presentation, complications, and outcomes were collected from national surveillance systems and local health facilities, with laboratory confirmation using quantitative PCR. All analyses were restricted to descriptive statistics. FINDINGS: Of 17 927 suspected cases identified, 10 986 were investigated, 5948 were PCR-positive, and 4895 met the inclusion criteria based on data completeness: 4436 in newly affected and 459 in endemic regions. In newly affected provinces, median age was 20 years (IQR 8-28), 2119 (47·8%) participants were female, and 2310 (52·1%) were male. In endemic provinces, median age was 15 years (7-26), 179 (39·0%) participants were female, and 277 (60·3%) were male. Direct or intimate human contact was reported by 1951 (44·0%) individuals in newly affected provinces versus 25 (5·4%) in endemic provinces, and zoonotic exposure in 11 (0·2%) and 99 (21·6%), respectively. The proportions of partcipants with systemic symptoms (3828 [86·3%] in newly affected provinces and 427 [93·0%] in endemic provinces) and respiratory symptoms (2450 [55·2%] and 219 [47·7%]), and median skin lesion counts (91 [IQR 37-200] and 163 [95-345]) were similar between newly affected and endemic regions. Complications included skin infections (2041 [46·0%] in newly affected provinces and 201 [43·8%] in endemic provinces), respiratory distress (82 [1·8%] and 29 [6·3%]), vision impairment (7 [0·2%] and 28 [6·1%]), and prostration (695 [15·7%] and 51 [11·1%]). The case-fatality rate was 0·7% (95% CI 0·4-1·3
14 of 1924) in children and 0·6% (0·3-1·0
14 of 2483) in adults in newly affected areas, compared with 5·9% (3·4-10·0
14 of 236) in children and 2·7% (1·1-6·1
six of 222) in adults in endemic regions. Content note: this Article and its appendix contain graphic images of mpox lesions affecting various sites including the face and genitals. INTERPRETATION: Our study indicates concurrent mpox outbreaks in DR Congo, involving younger individuals, a higher proportion of women and girls, and distinct presentations with higher lesion counts and respiratory symptoms compared with clade 2b lineage B.1 outbreaks. The high proportion of infectious complications and case-fatality rates, especially in endemic regions, emphasise the need for timely antibiotic therapy and targeted vaccination to reduce morbidity and mortality. FUNDING: Skin NTDs and STI Research Unit, Fight Infections Foundation.