Smokers have unexplained lower cardiac mortality than non-smokers in the short term following acute myocardial infarction (AMI). We hypothesized that smokers may have enhanced systemic fibrinolysis following thrombolysis. We studied 185 consecutive patients receiving thrombolysis for first AMI. Cardiac mortality at 36 days after thrombolysis was 11.9% (22 deaths). Factors associated with cardiac mortality were: smoking (current 3.4% mortality, previous 11.4%, never 24.2%) (p < 0.001); post-thrombolysis plasma fibrinogen at 60 min (p < 0.05); diabetes (p < 0.005); age (p < 0.01); time to thrombolysis (p < 0.05); and ECG evidence of reperfusion (p < 0.05). In logistic regression analysis, smokers were at significantly lower risk of cardiac death compared with non-smokers: unadjusted odds ratio (OR) 0.3 (95% CI 0.2-0.7) (p < 0.01). This was independent of age, diabetes, ECG evidence of reperfusion and pain to treatment time: OR 0.4 (95% CI 0.3-0.9) (p < 0.05). Smoking was not an independent prognostic factor after adjustment for post-thrombolysis plasma fibrinogen OR 0.5 (95% CI 0.4-1.1) (p = 0.1), although its insignificance may be due to lack of numbers. In non-smokers, there was a subgroup with persistent ST elevation, high post-thrombolysis fibrinogen and 40% short-term mortality. No similar high-risk sub-group was observed in smokers. Smoking was associated with lower mortality in patients receiving thrombolysis for first AMI, and post-thrombolysis fibrinogen concentrations were associated with this beneficial effect. Although patient numbers are small, and the hypothesis should be tested further in a larger group, the higher likelihood of incomplete reperfusion and of incomplete fibrinolysis in non-smokers supports the hypothesis that smokers may have enhanced systemic fibrinolysis following thrombolysis in AMI.