Abstract Background: East Africa is affected by a disproportionately high burden of esophageal squamous cell carcinoma (ESCC). Methods: We conducted an incident case–control study in Dar es Salaam, Tanzania with 1:1 matching for gender and age. A questionnaire evaluated known and putative risk factors for ESCC. Cochran–Mantel–Haenszel and multivariable conditional logistic regression analyses were applied to evaluate associations with ESCC risk, with adjustment for geographic zone. Results: Of 471 cases and 471 controls, the majority were male (69%); median ages were 59 and 55, respectively. In a multivariable logistic regression model, a low International Wealth Index (IWI) score [OR 2.57; 95% confidence interval (CI), 1.41–4.68], former smoking (OR 2.45; 95% CI, 1.46–4.13), second-hand smoke in the household (OR 1.67; 95% CI, 1.01–2.77), daily spicy chilies (OR 1.62; 1.04–2.52), and daily salted foods (OR 2.02; 95% CI, 1.06–3.85) were associated with increased risk of ESCC. Daily consumption of raw greens (OR 0.36; 95% CI, 0.16–0.80), fruit (OR 0.47; 95% CI, 0.27–0.82), and smoked fish (OR 0.31; 95% CI, 0.15–0.66) were protective. Permanent residence in the Central (OR 5.03; 95% CI, 2.16–11.73), Northern-Lake (OR 2.40; 95% CI, 1.46–3.94), or Southern Highlands zones (OR 3.18; 95% CI, 1.56–6.50) of Tanzania were associated with increased risk compared with residence in the Eastern zone. Conclusions: Low IWI score, smoke exposure(s), geographic zone, and dietary factors were associated with risk for ESCC in Tanzania. Impact: These findings will inform the development of future hypothesis-driven studies to examine risk factors for the high burden of ESCC in East Africa. See related commentary by McCormack et al., p. 248