Poomukhappadiyil Ninneyum Kathu movie revolves around Dr. Isaac (Mammootty) who has a jealous wife (Srividhya) who constantly suspects him of philandering. When an attractive young woman with a correspondingly jealous husband (Thilakan) moves into the neighboring house, tensions rise. The respective children of the two bickering couples (Rehman and Sisily) start a little romance of their own, which complicates matters further since one family is Hindu, the other Christian, and both sets of parents are opposed to the alliance.

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