Background Cardiovascular disease (CVD) is the leading cause of death among non-communicable diseases in South Africa. Several metabolic risk factors contribute to the development of CVD. Informal workers such as waste pickers could be unhealthy lifestyle naive, and most public health research on CVD does not include this understudied population. This study estimated the 10-year risk of fatal CVD and its association with metabolic risk factors in an understudied study population of waste pickers in Johannesburg, South Africa. MethodsA cross-sectional survey was conducted among waste pickers in two landfill sites in Johannesburg. We used the Systematic Coronary Risk Evaluation (SCORE) risk charts to estimate the 10-year risk of fatal CVD. We then employed ordinary least squares regression to assess the association between the 10-year risk of fatal CVD with metabolic risk factors. Other variables adjusted in the regression model were HIV status, education, income, injuries from work, clinic visits in the previous 12 months, and alcohol consumption. ResultsA total of 370 waste pickers were included in this analysis, 265 (73.41%) were males. The mean age of the participants was 34 years. The majority were between the age of 20 and 39 years. More than 55% of the waste pickers did not visit a clinic in the previous 12 months, and 68.57% were smoking. The 10-year survival probability from CVD was more than 99% for both males and females. Waste pickers who were overweight/obese, hypertensive, or with an elevated blood glucose level had high statistically significant mean percentages of the 10-year risk of fatal CVD compared to those who did not have the metabolic risk factors. Conclusions Prevention of 10-year risk of fatal CVD in this understudied population of waste pickers should target the control of obesity, hypertension, and diabetes. Health awareness and education for waste pickers will be an important step in reducing the burden of these metabolic risk factors. We further recommend that health systems should recognize waste pickers as a high-risk group and consider extensive CVDs surveillance.