A cross-sectional exploratory assessment of the factors that influence process safety cumulative risk for accident prevention in petroleum operations in Niger-Delta Nigeria was investigated. For the study, a purposive cum random sampling technique was deployed among selected petroleum companies operating in Niger-Delta, Nigeria. A population of 261 of asset integrity engineers/operators, process safety experts, production safety professionals in the petroleum industry in the Niger Delta were sampled using survey questionnaires. Descriptive and inferential statistics (analysis of variance) were used for data analysis. Overall, the study established that process safety cumulative risk assessment has a significant influence in major accident prevention in petroleum operations in Niger-Delta, Nigeria. The study identified seven influencing factors that need to be considered by petroleum industries in Niger-Delta Nigeria, in assessing process safety cumulative risk: (a) preventive and corrective maintenance deviations (agreed by 100% of the respondents), (b) temporary changes (agreed by 98% of the respondents), (c) inhibits/overrides (agreed by 96% of the respondents. Also (d) 97% accounted for downgraded integrity items and (e) 100% accounted for permit to work as influencing factors. The study further showed that (f) simultaneous operations (averred by 99% of the respondents) and (g) open actions from safety review /audits (averred by 92% of the respondents) were the other influencing factors. Including these influencing factors in process safety cumulative risk assessment by the petroleum industries in the study area, will enable better operational decision making in reducing the risk of major accidents.