Although smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are often accompanied by increased peripheral muscle fatigability, the extent to which this is a feature of the disease or a direct effect of smoking per se is not known. Skeletal muscle function was investigated in terms of maximal voluntary isometric torque, activation, contractile properties and fatigability, using electrically evoked contractions of the quadriceps muscle of 40 smokers [19 men and 21 women; mean (SD) cigarette pack years: 9.9 (10.7)] and age- and physical activity level matched non-smokers (22 men and 23 women). Maximal strength and isometric contractile speed did not differ significantly between smokers and non-smokers. Muscle fatigue (measured as torque decline during a series of repetitive contractions) was greater in smokers (P = 0.014), but did not correlate with cigarette pack years (r = 0.094, P = 0.615), cigarettes smoked per day (r = 10.092, P = 0.628), respiratory function (%FEV(1pred)) (r = -0.187, P = 0.416), or physical activity level (r = -0.029, P = 0.877). While muscle mass and contractile properties are similar in smokers and non-smokers, smokers do suffer from greater peripheral muscle fatigue. The observation that the cigarette smoking history did not correlate with fatigability suggests that the effect is either acute and/or reaches a ceiling, rather than being cumulative. An acute and reversible effect of smoking could be caused by carbon monoxide and/or other substances in smoke hampering oxygen delivery and mitochondrial function.