BACKGROUND: Cellulitis is a common infection of the skin and subcutaneous tissues. It is associated with significant morbidity from necrosectomies and amputations especially in sub-Saharan Africa. We aimed at identifying the risk factors and burden of lower limb cellulitis to inform preventive strategies in Cameroon. METHODS: This was a hospital-based case-control study carried out in the Bamenda Regional Hospital (BRH) between September 2015 and August 2016. Cases were defined as consenting adults admitted to the surgical unit who presented with a localised area of lower limb erythema, warmth, oedema and pain, associated with fever (temperature ≥ 38 °C) and/or chills of sudden onset. Controls were adults hospitalised for diseases other than cellulitis, necrotising fasciitis, myositis, abscess or other variants of dermo-hypodermitis. Cases and controls were matched (1:2) for age and sex. RESULTS: Of the 183 participants (61 cases of cellulitis and 122 controls) included in the study, the median age was 52 years [Interquartile range (IQR): 32.5-74.5]. After controlling for potential confounders, obesity [adjusted odds ratio (AOR) = 4.7, 95% CI (1.5-14.7); p = 0.009], history of skin disruption [AOR = 12.4 (3.9-39.1); p < 0.001], and presence of toe-web intertrigo [AOR = 51.4 (11.7-225.6); p < 0.001] were significantly associated with cellulitis. Median hospital stay was longer (14 days [IQR: 6-28]) in cases compared to the controls (3 days [IQR: 2-7]). Among the cases, Streptococci species were the most frequent (n = 50, 82%) isolated germ followed by staphylococci species (n = 9, 15%). Patients with cellulitis were more likely to undergo necrosectomy (OR: 21.2; 95% CI: 7.6-59.2). Toe-web intertrigo had the highest (48.9%) population attributable risk for cellulitis, followed by history of disruption of skin barrier (37.8%) and obesity (20.6%). CONCLUSION: This study showed a high disease burden among patients with cellulitis. While risk factors identified are similar to prior literature, this study provides a contextual evidence-base for clinicians in this region to be more aggressive in management of these risk factors to prevent disease progression and development of cellulitis.