Abstract Background In 2002 the oil-tanker Prestige sank off the Galician coast. This study analyzes the effect of this accident on health-related quality of life (HRQoL) and mental health in the affected population. Methods Using random sampling stratified by age and sex, 2700 residents were selected from 7 coastal and 7 inland Galician towns. Two exposure criteria were considered: a) residential exposure, i.e., coast versus interior; and b) individual exposure-unaffected, slightly affected, or seriously affected-according to degree of personal affectation. SF-36, GHQ-28, HADS and GADS questionnaires were used to assess HRQoL and mental health. Association of exposure with suboptimal scores was summarized using adjusted odds ratios (OR) obtained from logistic regression. Results For residential exposure, the SF-36 showed coastal residents as having a lower likelihood of registering suboptimal HRQoL values in physical functioning (OR:0.69; 95%CI:0.54–0.89) and bodily pain (OR:0.74; 95%CI:0.62–0.91), and a higher frequency of suboptimal scores in mental health (OR:1.28; 95%CI:1.02–1.58). None of the dimensions of the other questionnaires displayed statistically significant differences. For individual exposure, no substantial differences were observed, though the SF-36 physical functioning dimension rose (showed better scores) with level of exposure (91.51 unaffected, 93.86 slightly affected, 95.28 seriously affected, p < 0.001). Conclusion Almost one and a half years after the accident, worse HRQoL and mental health levels were not in evidence among subjects exposed to the oil-spill. Nevertheless, some of the scales suggest the possibility of slight impact on the mental health of residents in the affected areas.