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Production of peanut (Arachis hypogaea L.) in reduced tillage systems has increased in the United States during the past decade. However, interactions of tillage system and crop rotation have not been thoroughly investigated for large-seeded, Virginia market type peanut. Research was conducted at two locations in North Carolina during 1999 to 2006 to compare yield of corn (Zea mays L.), cotton (Gossypium hirsutum L.), and peanut in different rotations planted in conventional and reduced tillage. Crop rotation affected peanut yield but did not affect corn or cotton yield. Increasing the number of times corn, cotton, or a combination of these crops were planted between peanut increased peanut yields. Tillage affected cotton and peanut yield but not in every year or at both locations. Yield was similar in conventional and reduced tillage in 8 of 10 comparisons (cotton) and 6 of 8 comparisons (peanut). Crop rotation and tillage did not interact for visual estimates of plant condition of peanut as a result of disease, soil parasitic nematode populations when peanut was planted during the final year of the experiment, crop yield, cumulative net return over the duration of the experiment, or bulk density in the pegging zone during the final year of the experiment. These data suggest that variation in response to rotation and tillage should be expected based on the crop and edaphic and environmental conditions. However, response to rotation and tillage most likely will be independent.