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Background: Studies from Finland and Taiwan have shown that walking against traffic was beneficial for reducing pedestrian crashes and fatalities. This study examined whether such beneficial effects are consistent across various circumstances. Methods: This study aimed to investigate pedestrian fatalities in walking-against or with-traffic crashes by analysing the UK STATS19 crash data for the period between 1991 and 2020. We firstly employed Chi-square tests to examine risk factors for pedestrian injury severity. These variables were then incorporated into stepwise logistic regression models with multiple variables. We subsequently conducted joint effect analysis to investigate whether the beneficial effects of walking against traffic on injury severity vary across different situations. Results: Our data contained 44,488 pedestrian crashes, of which 16,889 and 27,599 involved pedestrians walking against and with traffic, respectively. Pedestrians involved in with-traffic crashes were more likely to sustain fatalities (adjusted odds ratio [AOR] = 1.542; confidence interval [CI] = 1.139–1.927) compared with those in walking against-traffic crashes. The detrimental effect of walking with traffic on fatalities appeared to be more pronounced in darkness-unlit conditions (AOR = 1.48; CI = 1.29–1.70), during midnight hours (00:00–06:59 am) (AOR = 1.60; CI = 1.37–1.87), in rural areas (AOR = 2.20; CI = 1.92–2.51), when pedestrians were elderly (≥ 65 years old) (AOR = 2.65, CI = 2.16–3.26), and when heavy goods vehicles were crash partners (AOR = 1.51, CI = 1.28–1.78). Conclusions: Walking against traffic was beneficial in reducing pedestrian fatalities compared with walking with traffic. Furthermore, such a beneficial effect was more pronounced in darkness-unlit conditions, at midnights (00:00–06:59 am), in rural areas, when pedestrians were elderly, and when heavy goods vehicles struck pedestrians. [ABSTRACT FROM AUTHOR]