This study aimed at evaluating the influence of submaximal isometric contraction on pressure pain thresholds (PPTs) in 14 healthy volunteers before and after skin hypoesthesia. PPTs were determined with pressure algometry over m. quadriceps femoris before, during, and following an isometric contraction. Maximum voluntary contraction (MVC) was assessed using a computerized dynamometer. A contraction of 21% MVC was held until exhaustion (max: 5 min) and PPTs were assessed every 30 sec. A local anesthetic cream and a control cream were applied following a double-blind design and PPTs were reassessed. PPTs increased significantly at the start of contraction and continued to increase until the middle of the contraction period, then remaining at this level. After contraction PPTs decreased significantly but for 5 min remained slightly above precontraction levels. Anesthetic cream raised PPT at rest but not during and following contraction. The relative increase in PPTs during and immediately following isometric contraction was lower with anesthetic cream. Isometric contraction of m. quadriceps femoris increase PPTs during and following contraction. The results suggest that input from cutaneous and deeper tissues interacts with nociceptive activity set up by the pressure stimulus. Determining the degree of sensory modulation in muscle and skin in different chronic pain syndromes could become a functional method of patient assessment important for differential diagnosis, treatment evaluation, and follow-up.