As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.