Most African populations are regularly exposed to biomass smoke, but knowledge of associated health implications is limited. This study aimed to investigate the association between oesophageal cancer (OC) and exposure to biomass smoke. This case-control study was conducted in Lusaka, Zambia. Cases were patients with endoscopically diagnosed OC, while controls were healthy volunteers. Questionnaires were used to collect lifestyle risk factors. Two sets of data were analysed; one with unmatched cases and controls and the other one with matching by age and sex. We enrolled 366 patients (131 cases and 235 controls). Among the cases, 50 (38%) were female and the median age was 56 years (IQR = 46-65 years). OC was significantly associated with domestic exposure to biomass smoke in univariate analysis (OR: 3.1; 95% CI: 1.7-5.6, p < 0.001) and after adjusting for potential confounders (OR: 2.1; 95% CI: 1.1-3.8, p = 0.017). Matched comparisons showed similar results for this association in univariate analysis (OR: 2.9; 95% CI: 1.5-5.8, p < 0.001) and using conditional logistic regression (OR: 2.8; 95% CI: 1.3-5.9, p = 0.005). Other risk factors found to be associated with OC were rural residence (OR: 2.3; 95% CI: 1.0-5.3, p = 0.004), lack of formal education (OR: 3.9; 95% CI: 1.5-9.9, p = 0.04) and living in poor housing (OR: 2.4; 95% CI: 1.1-5.6, p = 0.034). In conclusion, there is an association between OC and domestic exposure to biomass smoke and other lifestyle factors linked to low socio-economic status.